JP7046959B2 - Thienopyrimidine derivatives and their use in pharmaceuticals - Google Patents

Description

Cross-reference of related applications

This application provides the priority and interests of Chinese Patent Application No. 201710052275.3 filed with the National Intellectual Property Office of the People's Republic of China on January 22, 2017, which is incorporated herein by reference in its entirety. Insist.

Field of invention

INDUSTRIAL APPLICABILITY The present invention relates to a thienopyrimidine derivative having an enzyme-inhibiting activity and a pharmaceutical composition thereof, and the compound and the composition can be used in the manufacture of a pharmaceutical for treating a disorder or disease controlled by acetyl-CoA carboxylase.

Background of the invention

Acetyl-CoA carboxylase (ACC) is a limiting enzyme in the first step of the fatty acid synthesis process and is a biotin-dependent enzyme that undergoes carboxylation of acetyl-CoA by the HCO ₃ ^- carboxyl donor in the presence of ATP and Mg ²⁺ . Produces malonyl coenzyme A.

This enzyme is associated with specific tissue enzymes in humans and other mammals, it has two subtypes ACC1 and ACC2, and there are some differences in tissue distribution and function between the two subtypes. ACC1 is generally expressed in all tissues, its expression level is highest in lipid-producing tissues (eg, liver and adipose tissue), and ACC2 is highest expression level in skeletal muscle and heart, and low expression level in liver. Has. Biosynthesis of long-chain fatty acids is catalyzed by ACC1, acetyl-CoA is metabolized in the Krebs circuit if it is carboxylated and does not produce malonyl-coenzyme A, and the production of malonyl-coenzyme A on the cytoplasmic surface of mitochondria is The amount of fatty acid catalyzed by ACC2 and used for β-oxidation is controlled by inhibiting carnitine palmitoyl transferase (CPT-1).

Studies have shown that ACC inhibitors can inhibit ACC1 to reduce fatty acid synthesis, and also inhibit ACC2 to promote fatty acid oxidation in the liver and then reduce lipid accumulation in vivo. This is due to obesity, hypertension, diabetes, tumors, dyslipidemia and hyperlipidemia, as well as lipid accumulation in the liver, non-alcoholic steatohepatitis (NAFLD) and non-alcoholic steatohepatitis (NASH). It has been shown to be able to effectively treat diseases and disorders associated with type II diabetes induced by insulin resistance.

Non-alcoholic steatohepatitis (NASH) is a chronic progressive disease induced by the accumulation of lipids in the liver, which can cause cirrhosis, liver failure and hepatocellular carcinoma. For example, enzymes associated with age, obesity, body mass index (BMI), insulin sensitivity, dyslipidemia, hypertension and abnormally active liver function (eg, alanine aminotransferase (ALT) and aspartate aminotransferase (AST)). ) And many other NASH inducers. It has been reported that the presence of affected individuals with symptoms of metabolic syndrome (mainly afferent obesity, hypertension, insulin resistance, high triglycerides, and low density lipoproteins) is positively associated with the risk of NASH. .. Liver biopsy results show that NASH is associated with severe fibrosis in 66% of diabetic or obese patients over the age of 50. About 12% of people in the United States are deeply affected by the disease, with a 22% increase in diabetes, and more importantly, about 15-25% of people with NASH suffer from liver cirrhosis. This may be another cause of liver cancer after viral and alcoholic hepatitis. Cirrhosis is the leading cause of death from liver disease, which is a direct cause of liver decompensation and a mortality rate of about 4% annually.

Other alternative therapies for obesity, hypertension, diabetes, and dyslipidemia are still needed, but current therapies are limited for NASH.

The present invention relates to a compound as an acetyl-CoA carboxylase (ACC) inhibitor and a pharmaceutical composition containing the present compound. The invention further relates to the use of the compound or compositions thereof in the manufacture of pharmaceuticals for inhibiting ACC activity and treating disorders and diseases. The present invention further describes a method for synthesizing the present compound. The compounds of the present invention exhibit good bioactivity and pharmacokinetic activity.

As used herein, inhibition of ACC refers to inhibition of ACC1 only, inhibition of ACC2 alone, or simultaneous inhibition of ACC1 and ACC2. Inhibition of any one of the ACC subtypes should have a favorable effect on disorders associated with metabolic syndrome. The optimized ACC inhibitor should inhibit both the isoenzymes of this enzyme.

（式中、
Ｈｅｔは、－Ｃ（＝Ｏ）ＮＲ^ａＲ^ｂ、－Ｃ（＝ＮＲ）ＮＲ^ａＲ^ｂ、－ＮＨ－Ｃ（＝ＮＲ）ＮＲ^ａＲ^ｂ、３～１０員のヘテロシクリル又は５～１０員のヘテロアリールであり、ここで、３～１０員のヘテロシクリル及び５～１０員のヘテロアリールの各々は、独立に及び任意に、Ｈ、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキル、カルボキシ及び－Ｃ（＝Ｏ）ＮＨ_２で置換されていてもよく、
Ｒ^１は、Ｈ、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ又はＣ_１－６ハロアルキルであり、
Ｒ^２は、－ＯＲ又は－ＮＲ^ａＲ^ｂであり、
Ｒ^３及びＲ^４の各々は、独立に、Ｈ、Ｄ、Ｃ_１－６アルキル、Ｃ_１－６ヒドロキシアルキル又はＣ_１－６ハロアルキルであり、
Ｌは、－Ｏ－、－Ｏ－メチレン－、－Ｏ－エチレン－、－Ｓ－又は－ＮＨ－であり、
Ｒ^５は、Ｃ_６－１０アリール又は５～１０員のヘテロアリールであり、ここで、Ｃ_６－１０アリール及び５～１０員のヘテロアリールの各々は、独立に及び任意に、１個、２個又は３個のＲ^６で置換されていてもよく、ここで、Ｒ^６は、Ｈ、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルキル、Ｃ_１－６ハロアルコキシ、Ｃ_１－６シアノアルキル又はＣ_１－６ヒドロキシアルキルであり、
Ｗは、縮合シクリル、架橋シクリル又はスピロシクリルであり、ここで、縮合シクリル、架橋シクリル又はスピロシクリルは、Ｎ、Ｏ又はＳから独立に選択される、０個、１個、２個、３個又は４個のヘテロ原子を含む飽和又は部分的に不飽和の６～１２員のシクリルであり、ここで、Ｗは、任意に、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、－Ｃ（＝Ｏ）ＯＲ、－Ｃ（＝Ｏ）ＮＲ^ａＲ^ｂ、－Ｃ（＝ＮＲ）ＮＲ^ａＲ^ｂ、－ＮＨ－Ｃ（＝ＮＲ）ＮＲ^ａＲ^ｂ、－ＳＯ_２Ｒ、－ＳＯ_２ＮＲ^ａＲ^ｂ、Ｃ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_１－６アルコキシ、Ｃ_１－６ハロアルコキシ、Ｃ_１－６アルキルアミノ、Ｃ_１－６ハロアルキル、Ｃ_１－６シアノアルキル及びＣ_１－６ヒドロキシアルキルから独立に選択される１個、２個、３個、４個又は５個の置換基で置換されていてもよく、
ここで、Ｒ、Ｒ^ａ及びＲ^ｂの各々は、独立に、Ｈ、Ｄ、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル又はＣ_３－８シクロアルキルであるか、又はＲ^ａ及びＲ^ｂは、それらが結合しているＮ原子と一緒に、３～１０員のヘテロシクリルを形成し、ここで、３～１０員のヘテロシクリルは、任意に、オキソ（＝Ｏ）、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ及びＣ_１－６ハロアルキルで置換されていてもよい）
を有する化合物又はその立体異性体、幾何異性体、互変異性体、Ｎ－オキシド、水和物、溶媒和物、代謝産物、薬学的に許容され得る塩若しくはプロドラッグが提供される。 In particular,
In one aspect, the specification herein is formula (I).

(During the ceremony,
Het is -C (= O) NR ^a R ^b , -C (= NR) NR ^a R ^b , -NH-C (= NR) NR ^a R ^b , 3 to 10-membered heterocyclyl or 5 to 10-membered heterocyclyl. Heteroaryl, where each of the 3-10 membered heterocyclyl and the 5-10 membered heteroaryl independently and optionally H, D, oxo (= O), F, Cl, Br, I, It may be substituted with hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, carboxy and —C (= O) NH ₂ .
R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl.
R ² is -OR or -NR ^a R ^b .
Each of R ³ and R ⁴ is independently H, D, C _1-6 alkyl, C _1-6 hydroxyalkyl or C _1-6 haloalkyl.
L is -O-, -O-methylene-, -O-ethylene-, -S- or -NH-, and
R5 is a C _6-10 aryl or a ^5-10 membered heteroaryl, where each of the C _6-10 aryl and the 5-10 membered heteroaryl is independently and optionally one, two. It may be substituted with 1 or 3 R ^6s , where R ⁶ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 cyanoalkyl or C _1-6 hydroxyalkyl.
W is a condensed cyclyl, a crosslinked cyclyl or a spirocyclyl, where the condensed cyclyl, the crosslinked cyclyl or the spirocyclyl is independently selected from N, O or S, 0, 1, 2, 3 or 4 Saturated or partially unsaturated 6-12 membered cyclyls containing heteroatoms, where W is optionally D, oxo (= O), F, Cl, Br, I, hydroxy, Amino, nitro, cyano, -C (= O) OR, -C (= O) NR ^a R ^b , -C (= NR) NR ^a R ^b , -NH-C (= NR) NR ^a R ^b ,- SO ₂ R, -SO ₂ NR ^a R ^b , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkyl amino, C _1-6 haloalkyl , C _1-6 cyanoalkyl and C _1-6 hydroxyalkyl may be substituted with 1, 2, 3, 4 or 5 substituents independently selected.
^Here , each of R, Ra and R ^b is independently H, D, C _1-6 alkyl, C _1-6 haloalkyl or C _3-8 cycloalkyl, or R ^a and R ^b are. , Together with the N atoms to which they are attached, form 3-10 membered heterocyclyls, where the 3-10 membered heterocyclyls are optionally oxo (= O), D, F, Cl, Br. , I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 haloalkyl may be substituted)
Provided are compounds having or steric isomers, geometric isomers, metavariants, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof.

In some embodiments, Het is a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, where each of the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl is independent. And optionally, H, D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, carboxy and -C (= O) NH ₂ may be substituted.

In some embodiments, Het is pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolysyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrizyl. , Pyrimidinyl, pyridazinyl or pyrazinyl, where pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolydyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl. , Pyridyl, pyrimidinyl, pyridadinyl and pyrazineyl, independently and optionally, H, D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, respectively. It may be substituted with methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, carboxy and -C (= O) NH ₂ .

In some embodiments, R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy or C _1-3 haloalkyl. ,
R ² is -OR or -NR ^a R ^b .
^Here , each of R, Ra and R ^b is independently H, D, C _1-3 alkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl, or R ^a and R ^b are. , Together with the N atoms to which they are attached, form a 4- to 6-membered heterocyclyl, where the 4- to 6-membered heterocyclyls are optionally oxo (= O), F, Cl, Br, I. , Hydroxy, Amino, Nitro, Cyano, C _1-3 Alkoxy, C _1-3 Alkoxy and C _1-3 Halo Alkyl may be substituted.
Each of R ³ and R ⁴ is independently H, D, C _1-3 alkyl, C _1-3 hydroxyalkyl or C _1-3 haloalkyl.

によって表されるヘテロシクリル基から選択されるヘテロシクリルを形成し、
ここで、式（ｉ－ａ）から（ｉ－ｋ）によって表されるヘテロシクリル基は、任意に、オキソ（＝Ｏ）、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、メチル、エチル、イソプロピル、メトキシ、エトキシ、トリフルオロメチル、ジフルオロメチル又はトリフルオロエチルで置換されていてもよく、
Ｒ^３及びＲ^４の各々は、独立に、Ｈ、Ｄ、メチル、エチル、ｎ－プロピル、ヒドロキシメチル、ヒドロキシエチル、トリフルオロメチル又は２－フルオロエチルである。 In some embodiments, R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl or tri. Fluoroethyl,
R ² is -OR or -NR ^a R ^b .
^{Here, each of R, Ra and R b independently} has H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Or R ^a and R ^b , together with the N atom to which they are attached, from formulas (Ia) to (i-k) :.

Forming a heterocyclyl selected from the heterocyclyl groups represented by
Here, the heterocyclyl group represented by the formulas (ia) to (ik) is optionally oxo (= O), D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, It may be substituted with methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl or trifluoroethyl.
Each of R ³ and R ⁴ is independently H, D, methyl, ethyl, n-propyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or 2-fluoroethyl.

In some embodiments, R5 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl or a ^5-6 membered heteroaryl, where phenyl, naphthyl, 1,2,3,4. -Each of the tetrahydronaphthyl and the ^5-6 membered heteroaryl may be independently and optionally substituted with one, two or three ^R6s , where R6 is H, D. , F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy, C _1-3 cyanoalkyl or C It is _1-3 hydroxyalkyl.

^In other embodiments, R5 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, frill, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl. Or pyridadinyl, where phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, frill, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranol and pyridadinyl. Each of each may be independently and optionally substituted with one, ^two or three ^R6s , where R6 is H, D, F, Cl, Br, I, hydroxy, Amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, hydroxyethyl, cyanomethyl or cyanoethyl.

のうち１つを有し、
Ｘ^１、Ｘ^２及びＸ^３の各々は、独立に、結合、－ＣＨ_２－、－Ｏ－、－Ｓ－又は－ＮＨ－であり、
Ｙは、ＣＨ又はＮであり、
ｒ、ｓ、ｔ及びｎの各々は、独立に、０、１、２又は３であり、
各Ｗは、任意に、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、－Ｃ（＝Ｏ）ＯＨ、－Ｃ（＝Ｏ）ＮＨ_２、－Ｃ（＝ＮＨ）ＮＨ_２、－ＮＨ－Ｃ（＝ＮＨ）ＮＨ_２、－ＳＯ_２ＣＨ_３、－ＳＯ_２Ｃ_２Ｈ_５、Ｃ_１－３アルキル、Ｃ_３－６シクロアルキル、Ｃ_１－３アルコキシ、Ｃ_１－３ハロアルコキシ、Ｃ_１－３アルキルアミノ、Ｃ_１－３ハロアルキル、Ｃ_１－３シアノアルキル及びＣ_１－３ヒドロキシアルキルから独立に選択される１個、２個、３個、４個又は５個の置換基で置換されていてもよい。 In some embodiments, W has the following structure:

Have one of
Each of X ¹ , X ² and X ³ is independently bound, -CH _2- , -O-, -S- or -NH-.
Y is CH or N,
Each of r, s, t and n is 0, 1, 2 or 3 independently.
Each W is optionally D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, -C (= O) OH, -C (= O) NH ₂ , -C. (= NH) NH ₂ , -NH-C (= NH) NH ₂ , -SO ₂ CH ₃ , -SO ₂ C ₂ H ₅ , C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy , C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkyl, C _1-3 cyanoalkyl and C _1-3 hydroxyalkyl independently selected 1, 2, 3, 4 It may be substituted with 15 or 5 substituents.

のうち１つを有し、
各Ｗは、任意に、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、－Ｃ（＝Ｏ）ＯＨ、－Ｃ（＝Ｏ）ＮＨ_２、－Ｃ（＝ＮＨ）ＮＨ_２、－ＮＨ－Ｃ（＝ＮＨ）ＮＨ_２、－ＳＯ_２ＣＨ_３、－ＳＯ_２Ｃ_２Ｈ_５、メチル、エチル、イソプロピル、ｎ－ブチル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、トリフルオロメチル、ジフルオロメチル、メトキシ、エトキシ、イソプロポキシ、トリフルオロメトキシ、ジフルオロメトキシ、メチルアミノ、シアノメチル及びヒドロキシメチルから独立に選択される１個、２個、３個、４個又は５個の置換基で置換されていてもよい。 In other embodiments, W has the following structure:

Have one of
Each W is optionally D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, -C (= O) OH, -C (= O) NH ₂ , -C. (= NH) NH ₂ , -NH-C (= NH) NH ₂ , -SO ₂ CH ₃ , -SO ₂ C ₂ H ₅ , methyl, ethyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , 1, 2, 3, 4 or 5 independently selected from trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, methylamino, cyanomethyl and hydroxymethyl. It may be substituted with a substituent.

In one aspect, the present specification refers to compounds of formula (I) or steric isomers, geometric isomers, metavariants, N-oxides, hydrates, solvates, metabolites, pharmaceuticals thereof. Provided are pharmaceutical compositions comprising acceptable salts or prodrugs, or pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles or combinations thereof.

In one aspect, the present specification describes a compound of formula (I) or a pharmaceutical composition thereof in the manufacture of a pharmaceutical for preventing, treating, treating or alleviating a disorder or disease controlled by acetyl-CoA carboxylase. The use of things is provided.

In some embodiments, the disorder or disease controlled by acetyl-CoA carboxylase disclosed herein is a metabolic or neoplastic disorder.

In other embodiments, the disorders or diseases controlled by acetyl-CoA carboxylase disclosed herein include insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic steatohepatitis and Includes non-alcoholic steatohepatitis.

In other embodiments, the neoplastic disorders disclosed herein are breast cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell bronchial cancer. , Includes endometrial cancer, colorectal cancer and prostate cancer.

In one aspect, herein is a compound of formula (I) or a pharmaceutical composition thereof for use in preventing, treating, treating or alleviating disorders or diseases controlled by acetyl-CoA carboxylase. Things are provided.

In some embodiments, the disorder or disease controlled by acetyl-CoA carboxylase disclosed herein is a metabolic or neoplastic disorder.

In other embodiments, the disorders or diseases controlled by acetyl-CoA carboxylase disclosed herein include insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic steatohepatitis and Includes non-alcoholic steatohepatitis.

In other embodiments, the neoplastic disorders disclosed herein are breast cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell bronchial cancer. , Includes endometrial cancer, colorectal cancer and prostate cancer.

In one aspect, the specification herein is a disorder or disease controlled by acetyl-CoA carboxylase in an affected body, comprising administering to the affected body a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof. Methods of prevention, treatment, treatment, or mitigation are provided.

In some embodiments, the disorder or disease controlled by acetyl-CoA carboxylase disclosed herein is a metabolic or neoplastic disorder.

In other embodiments, the disorders or diseases controlled by acetyl-CoA carboxylase disclosed herein include insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic steatohepatitis and Includes non-alcoholic steatohepatitis.

In other embodiments, the neoplastic disorders disclosed herein are breast cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell bronchial cancer. , Includes endometrial cancer, colorectal cancer and prostate cancer.

In another aspect, the present specification provides a method of preparing, separating or purifying a compound of formula (I).

The above is merely a summary of the particular aspects disclosed herein and is of course not intended to be limited. These aspects and other aspects as well as embodiments are described more fully below.

Detailed Description of the Invention Definitions and General Terms Here, certain embodiments of the invention are referred to in detail, examples of which are illustrated in the accompanying structures and formulas. The present invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the invention as defined by the claims. One of ordinary skill in the art will recognize many methods and substances similar to or equivalent to those described herein, which may be used in the practice of the present invention. The present invention is by no means limited to the methods and substances described herein. One or more of the incorporated documents, patents and similar materials may differ from or contradict this application, including, but not limited to, defined terms, use of terms, techniques described, etc. If so, this application governs.

As used herein, the following definitions apply, unless otherwise indicated. For the purposes disclosed in the present invention, chemical elements are specified according to the Periodic Table CAS version of the elements and the Handbook of Chemistry and Physics, 75th Ed. 1994. In addition, the general principles of organic chemistry are Sorrell et al., "Organic Chemistry", University Science Books, Sausalito: 1999, and Michael B. Smith et al., "March's Advanced Organic Chemistry", John Wiley & Sons, New York. : 2007, the entire contents of which are incorporated herein by reference.

The term "contains" means open, including the indicated components, but does not exclude other components.

As described herein, the compounds disclosed herein are optionally one or more substituents, eg, generally exemplified below, or specific classes, subclasses and of the invention. It may be substituted with that exemplified by Species. It will be appreciated that the phrase "may be optionally replaced" is used interchangeably with the phrase "replaced or not replaced". In general, the term "substituted" refers to substituting one or more hydrogen groups in a given structure with a group of a particular substituent. Unless otherwise specified, a group that may be optionally substituted may have a substituent at each substitutable position of the group. If two or more positions in a given structure can be substituted with two or more substituents selected from a particular group, the substituents are the same or different at each position. Substituents described herein are, but are not limited to, H, F, Cl, Br, I, nitro, cyano, oxo (= O), hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkyl. , Haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyl-oxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH, -alkylene-C (= O) O-alkyl, -alkylene- S (= O) ₂ -alkyl, -alkylene-S (= O) ₂ -amino, -S (= O) ₂ -alkyl, -S (= O) ₂ -amino, -S (= O) ₂ OH, -O-alkylene-C (= O) O-alkyl, -O-alkylene-S (= O) ₂ -alkyl, -O-alkylene-S (= O) ₂ -amino, -O-alkylene-S (=) O) ₂ OH, -C (= O) NH ₂ , -C (= O) NH-alkyl, -C (= O) N (alkyl) -alkyl, -C (= O) NHS (= O) _2- Alkoxy, -C (= O) NHS (= O) ₂ -amino, -C (= O) NHS (= O) ₂ OH, -N (haloalkyl) -alkyl, -N (alkyl) -S (= O) ₂ -alkyl, -NHS (= O) ₂ -alkyl, -NHS (= O) ₂ -haloalkyl, -N (alkyl) S (= O) ₂ -haloalkyl, -N (alkyl) S (= O) _2- Alkoxyamino, -NHC (= O) -alkyl, -NHC (= O) -haloalkyl, -N (alkyl) C (= O) -haloalkyl, -N (alkyl) C (= O) -alkylamino, -N (Alkoxy) C (= O) O-alkyl, -NHC (= O) O-alkyl, -NHC (= O) O-haloalkyl, -N (alkyl) C (= O) O-haloalkyl, -N (alkyl) ) C (= O) O-aminoalkyl, -NHC (= O) -NH ₂ , -NHC (= O) NH- (alkyl), -NHC (= O) NH (haloalkyl), -NHC (= O) N (alkyl) -alkyl, -OC (= O) -alkyl, -OC (= O) -amino, -OC (= O) -alkylamino, -OC (= O) -aminoalkyl, -OC (= O) ) -Alkoxy, -C (= O) N (alkyl) S (= O) ₂ -alkyl, -C (= O) N (alkyl) S (= O) ₂ -amino, -C (= O) NH- S (= O) ₂ OH, -C (= NH) NH ₂ , -C (= NH) NH-alkyl, -C (= NH) N (alkyl) -alkyl, -C (= N-alkyl) -NH ₂ , -C (= O) NH-alkylene-S (=) O) ₂ OH, -C (= O) NHC (= O) OH, -C (= O) NHC (= O) O-alkyl, -C (= O) N (alkyl) C (= O) O- It can be alkyl, —C (= O) NH-alkylene-C (= O) OH and —C (= O) NH-alkylene-C (= O) O-alkyl and the like.

The term "alkyl" or "alkyl group" refers to 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 A saturated linear or branched monovalent hydrocarbon group of up to 3 carbon atoms or 1 to 2 carbon atoms, wherein the alkyl group is optionally and independently one or more of those described herein. It may be substituted with a substituent of. Non-limiting examples of alkyl groups are methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i). -Pr, -CH (CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH (CH ₃ ) ₂ ), sec- Butyl (s-Bu, -CH (CH ₃ ) CH ₂ CH ₃ ), tert-butyl (t-Bu, -C (CH ₃ ) ₃ ), n-pentyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) ), 2-Pentyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3-Pentyl (-CH (CH ₂ CH ₃ ) 2), 2-Methyl-2-butyl (-C (CH ₃ ) ₂ ) CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl-l-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2 -Methyl-l-butyl (-CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH (CH ₃ )) CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH (CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ ), 3-Methyl-3-pentyl (-C (CH ₃ ) (CH ₂ CH ₃ ) 2), 2-Methyl-3-pentyl (-CH (CH ₂ CH ₃ ) CH (CH ₃ ) ₂ ) , 2,3-Dimethyl-2-butyl (-C (CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH (CH ₃ ) C (CH ₃ ) ₃ , n -Including heptyl and n-octyl and the like. The term "alkyl" or the prefix "alkal" includes both linear and branched saturated carbon chains. The term "alkylidene" or "alkylene" as used herein. For the removal of two hydrogen atoms from linear or branched saturated hydrocarbons. Thus, it refers to a saturated divalent hydrocarbon group derived. Examples of alkylene groups include, but are not limited to, methylene, ethylene, isopropylene and the like.

The term "alkenyl" refers to at least one unsaturated, i.e., carbon-carbon, 2 to 12 carbon atoms with sp ² double bonds, or 2 to 8 carbon atoms, or 2 carbon atoms. Refers to a linear or branched monovalent hydrocarbon group of up to 6 carbon atoms, or 2 to 4 carbon atoms, where the alkenyl group is independently unsubstituted or unsubstituted. It may be substituted with one or more substituents disclosed herein, including groups with "cis" and "trans" configurations, or instead "E" and "Z" configurations. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH ₂ ), allyl (-CH ₂ CH = CH ₂ ), butenyl (-CH ₂ CH ₂ CH = CH ₂ ) and the like.

The term "alkynyl" refers to at least one unsaturated site, ie, carbon-carbon, 2 to 12 carbon atoms with sp triple bonds, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms. Refers to a linear or branched monovalent hydrocarbon group of up to 4 carbon atoms, or 2 to 4 carbon atoms, where the alkynyl group is independent, unsubstituted or, as used herein. It may be substituted with one or more substituents disclosed in the document. Specific examples of the alkynyl group include, but are not limited to, ethynyl (-C≡CH) and propargyl (-CH ₂ C≡CH).

The term "heteroatom" refers to one or more of oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) and silicon (Si), nitrogen (N), sulfur (S), or phosphorus. Any oxidized form of (P); a primary, secondary, tertiary or quaternary ammonium salt; or a substitutable nitrogen of a heterocyclic ring, eg, N (3,4-dihydro). -Contains -C (= O) -of a heterocycle oxidized from -CH 2-), NH (in pyrrolidinyl) or NR (in N-substituted pyrrolidinyl); or _-CH2- .

The term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

The term "unsaturated" refers to a group having one or more unsaturated units.

The term "alkoxy" or "alkyl-oxy" refers to an alkyl group attached to another group in the molecule of a compound via an oxygen atom, as defined herein. In some embodiments, the alkoxy group is C _1-4 alkoxy. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy and butoxy and the like. Alkoxy groups may be optionally and independently substituted with one or more substituents disclosed herein.

The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, where alkoxy and alkyl are as defined herein. In some embodiments, the alkoxyalkyl is C _1-6 alkoxy-C _1-6 -alkyl. In other embodiments, the alkoxyalkyl is C _1-3 alkoxy-C _1-3 -alkyl. The "alkoxyalkyl" group may optionally be substituted with one or more substituents disclosed herein.

The terms "haloalkyl", "haloalkoxy" or "haloalkoxy" refer to alkyl, alkenyl or alkoxy which may optionally be substituted with one or more halogen atoms. In some embodiments, the haloalkyl is a halo C _1-6 alkyl. In other embodiments, the haloalkyl is halo C _1-3 alkyl. In some embodiments, the haloalkyl-oxy or haloalkoxy is halo C _1-6 alkyl-oxy or halo C _1-6 alkoxy. In other embodiments, the haloalkyl-oxy or haloalkoxy is halo C _1-3 alkyl-oxy or halo C _1-3 alkoxy. Some non-limiting examples of such groups include trifluoromethyl, difluoromethyl, 2-chloro-vinyl, 2,2-difluoroethyl, difluoromethoxy, trifluoromethoxy and the like. Also, optionally, each of haloalkyl, haloalkoxy or haloalkoxy may be optionally and independently substituted with one or more substituents described herein.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups. In some embodiments, the hydroxyalkyl is hydroxy C _1-6 alkyl. In other embodiments, the hydroxyalkyl is hydroxy C _1-3 alkyl. Some non-limiting examples include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. The "hydroxyalkyl" group may optionally be substituted with one or more substituents disclosed herein.

The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups. In some embodiments, the cyanoalkyl is a cyanoC _1-6 alkyl. In other embodiments, the cyanoalkyl is cyanoC _1-3 alkyl. Some non-limiting examples include cyanomethyl, 2-cyanoethyl, 3-cyanopropyl and the like. The "cyanoalkyl" group may optionally be substituted with one or more substituents disclosed herein.

The term "alkylamino" refers to "N-alkylamino" and "N, N-dialkylamino", where the amino groups are independently substituted with one or two alkyl groups, respectively. In some embodiments, the alkylamino is a C _1-6 alkylamino group. In other embodiments, the alkylamino is a C _1-3 alkylamino group. Some non-limiting examples of such groups include N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino and the like. Further, the alkylamino group may be optionally substituted with one or more substituents described in the present specification.

The term "cycloalkyl" or "cycloalkane" is a monovalent or polyvalent saturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic or tricyclic ring system but without an aromatic ring. To say. In some embodiments, the cycloalkyl group contains 3 to 10 carbon atoms. In other embodiments, the cycloalkyl group contains 3 to 8 carbon atoms. In yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. Some non-limiting examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The cycloalkyl group may optionally be substituted with one or more substituents disclosed herein.

The term "cycloalkyloxy" refers to a cycloalkyl group attached to the rest of the molecule via an oxygen atom. Cycloalkyl groups are as defined herein.

The term "cycloalkylalkyl" refers to a cycloalkyl group attached to the rest of the molecule via an alkyl group, wherein cycloalkyl and alkyl are as defined herein.

The terms "carbocyclyl", "carbon ring" or "carbon ring" are monovalent, polyvalent, non-aromatic with 3 to 12 carbon atoms as monocyclic, bicyclic or tricyclic hydrocarbons. Refers to a saturated or partially unsaturated ring of. The carbobicyclyl group includes a spirocarbobicyclyl group or a condensed carbobicyclyl group. Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. In one embodiment, the cycloalkyl group contains 4 to 8 carbon atoms. In other embodiments, the cycloalkyl group contains 4 to 6 carbon atoms. Further examples of carbocyclyl groups are cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-l-enyl, l-cyclopenta-2-enyl, l-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-l-enyl, l. -Cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundesyl, cyclododecyl and the like, and the cycloalkyl group is optionally described herein. May be substituted with one or more substituents disclosed in.

The terms "heterocycle", "heterocyclyl", or "heterocyclic ring" are used interchangeably herein and are 3 to 12 rings in which at least one atom is a heteroatom but does not contain an aromatic ring. A saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing an atom. In some embodiments, the "heterocyclyl" or "heterocycle" comprises 3-10 ring atoms, and in some embodiments, the "heterocyclyl" or "heterocycle" has 3-8 rings. In other embodiments, the "heterocyclyl" or "heterocycle" comprises 5-8 ring atoms, and in yet other embodiments, the "heterocyclyl" or "heterocycle" is 3-6. In still other embodiments, the "heterocyclyl" or "heterocycle" comprises 5-6 ring atoms, and in yet other embodiments, the "heterocyclyl" or "heterocycle" is. It contains 4 to 6 ring atoms and can be a heterocyclyl carbon group or a heteroatom group unless otherwise specified, the heteroatoms as defined herein. Non-limiting examples of heterocyclyl groups include oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazoridinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1 , 3-Dioxolanil, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, tioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, Includes oxazepinyl, diazepinyl, thiazepinyl, 2-oxa-5-azabicyclo [2.2.1] hepta-5-yl. Some non-limiting examples of heterocyclyls in which the -CH ₂ -group is replaced with the -C (= O) -group are 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl, Includes 3,5-dioxopiperidinyl, pyrimidinedione-yl and the like. Some non-limiting examples of heterocyclyl in which the sulfur ring atom is oxidized are sulfolanyl and 1,1-dioxo-thiomorpholinyl. The heterocyclyl group may optionally be substituted with one or more substituents disclosed herein.

The term "heterocyclylalkyl" refers to a heterocyclyl group attached to the rest of the molecule via an alkyl group, as heterocyclyl and alkyl are as defined herein.

The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of 6 to 14 or 6 to 12 or 6 to 10 ring members. Where at least one ring in the system is between aromatics, each ring in the system comprises 3 to 7 ring members and has one or more bonds to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aryl ring" or "fragrance". Examples of aryl rings can include phenyl, naphthyl and anthracene. Aryl groups may be optionally and independently substituted with one or more substituents disclosed herein.

The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of 5 to 12 or 5 to 10 or 5 to 6 ring members. Well, where at least one ring in the system is aromatic, at least one ring member is selected from heteroatoms, and each ring in the system contains from 5 to 7 ring members. It has one or more binding sites connected to the rest of the molecule. The terms "heteroaryl" and "aromatic heterocycle" or "heteroaromatic compound" may be used interchangeably herein. The heteroaryl group may optionally be substituted with one or more substituents disclosed herein. In one embodiment, the 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, where N may be oxidized.

Some non-limiting examples of heteroaryl rings are furanyl, imidazolyl (eg N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazoryl (eg 2-oxazolyl, 4-oxazolyl, 5). -Oxazolyl), pyrrolyl (eg N-pyrrolyl, 2-pyrryl, 3-pyrrylyl), pyridyl, pyrimidinyl (eg 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazolyl (eg 2-thiazolyl, 4-thiazolyl) , 5-thiazolyl), tetrazolyl (eg 5-tetrazolyl), triazolyl, thienyl (eg 2-thienyl, 3-thienyl), pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1, 2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiazylazolyl, 1,3,4-thiazialzolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following. Bicycles: benzoimidazolyl, benzofuryl, benzothienyl, indolyl (eg 2-indrill), prynyl, quinolinyl (eg 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), 1,2,3,4-tetrahydroisoquinolinyl , 1,3-benzodioxolyl, indolinyl, isoquinolinyl (eg 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazole [1,2-a] pyridyl, pyrazolo [1,5-a] pyrizyl, pyrazolo [ 1,5-a] pyrimidyl, imidazole [1,2-b] pyridadinyl, [1,2,4] triazolo [4,3-b] pyridadinyl, [1,2,4] triazolo [1,5-a] It contains pyrimidinyl, [1,2,4] triazolo [1,5-a] pyridyl and the like.

The term "condensed ring" or "condensed cyclyl" refers to a monovalent or polyvalent saturated or partially unsaturated fused ring system, which refers to a non-aromatic bicyclic ring system. The condensed ring system may be a condensed carbon ring or a condensed heterocycle. Such systems may include those that are single or conjugated unsaturated in their core structure but are not aromatic rings. Non-limiting examples of condensed cyclyls include octahydrocyclopentadienyl, hexahydro-1H-pyrrolidinyl, hexahydropyrro [2,1-b] oxazolyl, hexahydropyrro [2,1-c] oxazolyl, octahydrocyclo. Penteno [c] pyrrolyl, hexahydro-1H-cyclopenteno [c] frills, hexahydro-1H-flo [3,4-c] pyrrolyl, hexahydroflo [3,2-b] frills, tetrahydro-3aH-cyclopenteno [d] ] [1,3] Dioxolyl, Octahydro-1H-Indenyl, Hexahydro-2H-Oxazolo [3,2-a] Pyridyl, Decahydronaphthyl, Decahydroisoquinolyl, Decahydroquinolyl, Octahydro-2H-benzo [b] [1,4] Contains oxadinyl and the like. Further, here, the condensed cyclyl group may be optionally substituted with one or more substituents described in the present specification.

The term "spirocyclyl" or "spiro ring" refers to a monovalent or multivalent saturated or partially unsaturated ring system, which is a ring derived from a particular cyclic carbon of another ring. The spiro ring system may be a condensed carbon ring or a condensed heterocycle. Non-limiting examples of spirocyclyls are spiro [3.3] heptyl, 2-azaspiro [3.3] heptyl, 2,6-diazaspiryl [3.3] heptyl, 2-oxaspiro [3.3] heptyl, 2 -Oxa-6-azaspiro [3.3] heptyl, spiro [4.4] nonyl, 2-oxaspiro [4.4] nonyl, 1,4-dioxaspiro [4.4] nonyl, spiro [4.5] decyl , 2-Oxa-7-azaspiro [4.5] decyl, 2,7-dioxaspiro [4.4] nonyl and the like. Further, the spirocyclyl group may be optionally substituted with one or more substituents described in the present specification.

The term "crosslinked cyclyl" or "crosslinked ring" refers to a saturated or unsaturated crosslinked ring system, which is a non-aromatic bicyclic ring system. Such systems may contain non-aromatic ones, either alone or conjugated unsaturated in the core structure. The "crosslinked cyclyl" or "crosslinked ring" can be a crosslinked carbon ring or a crosslinked heterocycle, the heteroatom is selected from N, O, P and S, where S or P is optionally in one or more oxos. It may be substituted to provide the group SO or SO ₂ , PO or PO ₂ . Non-limiting examples of cross-linked cyclyls are bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, (1r, 4r) -bicyclo [2.1.1] hexyl, (1R, 5S). ) -Vicyclo [3.2.1] octyl, (1R, 5S) -8-azabicyclo [3.2.1] octyl, adamantane and the like. The "crosslinked cyclyl" or "crosslinked ring" may be substituted with the substituents disclosed herein.

本明細書に記載されるとき、環系内の１つの環の中心に接続する結合（式（ｂ）に示す）は、環の何れかの妥当で結合可能な位置における結合が、分子の残りに接続できることを示す。式（ｂ）は、オクタヒドロシクロペンテノ［ｃ］ピロール環の何れかの妥当で結合可能な位置が、分子の残りと接続可能であることを示す。

更に、別段指示のない限り、語句「…の各々は独立に」は、語句「各…及び…は独立に」と互換可能に用いられる。同じ記号により表された具体的な選択肢が、異なる基においてそれぞれ独立しているか、又は同じ記号によって表される具体的な選択肢が同じ群において独立していることが広く理解されるべきである。 As described herein, a bond drawn from a substituent to the center of one ring in the ring system indicates the substitution of the substituent at any substitutable or reasonable position on the ring. For example, formula (a) means the single or multiple substitution of substituent R at any substitutable or reasonable position on the pyridine ring.

As described herein, a bond connecting to the center of one ring in the ring system (represented in formula (b)) is such that the bond at any reasonable and connectable position in the ring is the rest of the molecule. Indicates that you can connect to. Formula (b) indicates that any valid and connectable position on the octahydrocyclopenteno [c] pyrrole ring is connectable to the rest of the molecule.

Further, unless otherwise specified, the phrase "each of ... is independent" is used interchangeably with the phrase "each ... and ... is independent". It should be widely understood that the specific choices represented by the same symbol are independent in different groups, or the specific choices represented by the same symbol are independent in the same group.

Unless otherwise indicated, the structures described herein are in the form of all isomers of the structure (eg, enantiomers, diastereomers, atropisomers, geometric or conformational isomers); eg, each asymmetric. It also means the R and S conformations for the center, the (Z) and (E) double-bound isomers, and the (Z) and (E) conformers. Accordingly, single stereochemical isomers of the compound and mixtures of enantiomers, diastereomers, or geometric isomers are included within the scope disclosed herein.

Unless otherwise stated, the structures and compounds described herein are the forms of all isomers of the structure (eg, enantiomers, diastereomers, geometric isomers (conformational isomers)), their N-oxides. , Hydrate, isomers, metabolites, pharmaceutically acceptable salts or prodrugs are contemplated. Therefore, a single conformational isomer, mirror image isomer, diastereoisomer, geometric isomer, conformational isomer, its N-oxide, hydrate, solvent, metabolite, pharmaceutical Acceptable salts or prodrugs are included within the scope disclosed herein. In addition, unless otherwise stated, the structures described herein are also contemplated to contain compounds that differ only in the presence of one or more isotope-enriched atoms.

The "metabolites" described herein exhibiting activity similar to the compounds of formula (I) in vivo or in vitro are the metabolism of a particular compound or a pharmaceutically acceptable salt, analog or derivative thereof in the body. It is a product produced by. The metabolites of the compounds can be identified using routine techniques known in the art and their activity is determined using tests such as those described herein. Such products can result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, esterification, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds disclosed herein, including metabolites produced by contacting the compounds disclosed herein with a mammal for a sufficient period of time.

The definitions and conventions of stereochemistry used herein generally refer to SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen. , S., "Stereochemistry of Organic Conpounds", John Wiley & Sons, Inc., New York, 1994. The compounds disclosed herein may comprise an asymmetric center or a chiral center and thus may be present in different stereoisomers. All of the compounds disclosed herein include, but are not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as, but not limited to, racemic mixtures. It is contemplated that the stereoisomeric morphology forms part of the present invention. Many organic compounds exist in optically active form, i.e. they have the ability to rotate plane-polarized planes. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute arrangement of the molecule with respect to its chiral center. The prefixes d and l, or (+) and (-) are used to indicate the symbol of rotation of plane polarization by the compound, where (-) or l means that the compound is left-handed. Compounds preceded by (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical, except that they are mirror images of each other. Certain stereoisomers may also refer to enantiomers, but mixtures of such stereoisomers are referred to as enantiomeric mixtures. Certain stereoisomers are referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers refers to a racemic mixture or racemate, which can occur in the absence of stereoselectivity or stereospecificity in a chemical reaction or process. The term "racemic mixture" or "racemic" refers to an equimolar mixture of two enantiomers lacking optical activity.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted through a low energy barrier. Some non-limiting examples of proton tautomers (also known as prototropy tautomers) include interconversion through proton transfer, such as keto-enol and imine-enamine isomerization. .. Valence tautomers include interconversion by reorganization of some bound electrons.

"Pharmaceutically acceptable salt" refers to an organic or inorganic salt of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. Describe in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66: 1-19, which is incorporated herein by reference. Some non-limiting examples of pharmaceutically acceptable non-toxic salts are with inorganic salts such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or acetic acid, oxalic acid, maleic acid. Includes salts of amino groups produced with organic acids such as tartrate, citric acid, succinic acid and malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts are adipates, malate, 2-propionate, alginate, ascorbate, asparagate, benzenesulfonate, benzoate, hydrogensulfate, boro. Acids, butyrate, cypress salt, camphor sulfonate, cyclopentanepropionate, digluconsan salt, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate , Gluconate, hemisulfate, heptaneate, hexaneate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate , Malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, Includes picphosphate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonic acid, undecanoate, valerate and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternization of the basic nitrogen-containing groups of any of the compounds disclosed herein. Water or oil soluble or dispersible products can be obtained by such quaternization. Typical alkaline or alkaline earth metals used for salt formation include sodium, lithium, potassium, calcium, magnesium and the like. In addition, pharmaceutically acceptable salts are, where appropriate, non-toxic produced using counterions such as halides, hydroxydos, carboxylates, sulfates, phosphates, nitrates, C _1-8 sulfonates or aryl sulfonates. Includes sex ammonium, quaternary ammonium, and amine cations.

The term "hydrate" refers to a mixture in which the solvent molecule is water.

The term "solvate" refers to an aggregate or complex of one or more solvent molecules and the compounds disclosed herein. Non-limiting examples of solvents that produce solvates include water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid and ethanolamine.

An "ester" is an ester of a compound of formula (I) that contains a hydroxy group and is hydrolyzable in vivo, eg, a pharmaceutically acceptable ester that hydrolyzes in the body of a human or animal to produce a parent alcohol. say. Some non-limiting examples of hydrolyzable esters that produce groups for hydroxy in vivo are phosphate, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, Includes dialkylcarbamoyl, N- (dialkylaminoethyl) -N-alkylcarbamoyl and the like.

"N-oxide" refers to one or more nitrogen atoms that are oxidized to produce N-oxide, where the compound comprises several amine functional groups. Specific examples of N-oxides are N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be produced by treatment of the corresponding amines with an oxidizing agent such as, for example, hydrogen peroxide or a peracid (eg, peroxycarboxylic acid) (Advanced Organic Chemistiy, by Jerry March, 4th Edition,). See Wiley Interscience, pages). More specifically, N-oxides can be made by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), where the amine compound is inert, eg, dichloromethane. In the solvent, it is reacted with m-chloromethchloroperbenzoic acid (MCPBA).

The term "prodrug" refers to a compound that is converted in vivo to the compound of formula (I). Such conversions can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic conversion to the original form in blood or tissue. The prodrugs of the compounds disclosed herein can be, for example, esters. Some common esters used as prodrugs are phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonates, carbamate, and amino acid esters. For example, a compound disclosed herein that contains a hydroxy group can be acylated in its prodrug form at this position. Other prodrug forms include, for example, phosphates such as phosphate compounds derived from phosphorylation of the hydroxy group of the parent compound. A thorough discussion of prodrugs is available with T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceuticals. Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal. Provided in Chemistry, 2008, 51, 2328-2345, all of which are incorporated herein by reference in their entirety.

The term "protecting group" or "PG" refers to a substituent commonly used to block or protect a particular functionality while reacting with other functional groups of the compound. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality of a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxy-carbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects hydroxy functionality. Suitable protecting groups include methyl, methoxymethyl, acetyl, silyl and the like. "Carboxy protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Common carboxy protecting groups are -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy-methyl-l, 2- (p-toluenesulfonic acid) ethyl, 2- It contains (p-nitrophenylsulphenyl) -ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. See TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991, and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005 for a general description of protecting groups and their use.

The term "therapeutically effective amount" refers to the amount of compound of formula (I) sufficient to achieve the described effect. Therefore, a therapeutically effective amount of the compound of formula (I) used for the treatment of a disease controlled by ACC will be sufficient for the treatment of a disease controlled by ACC.

As used herein, the term "non-alcoholic steatohepatitis (NAFLD)" refers to insulin resistance, including simple fatty liver (SFL), non-alcoholic steatohepatitis (NASH), fatty liver fibrosis and cirrhosis. Refers to metabolic disorders associated with.

As used herein, the term "ACC inhibitor" refers to a substituent that can bind to and inhibit its activity.

"One (a)", "one (an)", "the" and similar terms used in the context of the present invention (especially in the context of the claims) are referred to in the book. Unless otherwise specified in the specification or clearly inconsistent with the context, it is intended to include both single and plural.

Description of the Compounds of the Invention The invention provides a compound or a pharmaceutical composition thereof, which can be an ACC inhibitor. The invention further relates to the use of a compound or composition thereof in the manufacture of a pharmaceutical for inhibiting ACC activity and treating a disorder or disease. The present invention further describes a method for synthesizing a compound. The compounds of the present invention exhibit good bioactivity and pharmacokinetic properties.

（式中、Ｈｅｔ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｌ及びＷは、本明細書に定義したとおりである）
を有する化合物又はその立体異性体、幾何異性体、互変異性体、Ｎ－オキシド、水和物、溶媒和物、代謝産物、薬学的に許容され得る塩若しくはプロドラッグが提供される。 In one aspect, the specification herein is formula (I).

(In the formula, Het, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L and W are as defined herein).
Provided are compounds having or isomers thereof, geometric isomers, metavariants, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs.

In some embodiments, the Het is -C (= O) NR ^a R ^b , -C (= NR) NR ^a R ^b , -NH-C (= NR) NR ^a R ^b , 3-10 members. Heterocyclyl or 5-10 membered heteroaryl, where each of the 3-10 membered heterocyclyl and the 5-10 membered heteroaryl is independently and optionally H, D, oxo (= O), F. , Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, carboxy and —C (= O) NH ₂ . , ^{Ra and R b are} as defined herein.

In some embodiments, R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl. ..

In some embodiments, R ² is -OR or -NR ^a R ^b , and R, ^{Ra and R b are} as defined herein.

In some embodiments, R is H, D, C _1-6 alkyl, C _1-6 haloalkyl or C _3-8 cycloalkyl.

In some embodiments, ^Ra is H, D, C _1-6 alkyl, C _1-6 haloalkyl or C _3-8 cycloalkyl.

In some embodiments, ^Rb is H, D, C _1-6 alkyl, C _1-6 haloalkyl or C _3-8 cycloalkyl.

In some embodiments, Ra and R ^b form a ^3-10 membered heterocyclyl together with the N atom to which they are attached, where the 3-10 member heterocyclyl is optionally. It may be substituted with oxo (= O), D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 haloalkyl.

In some embodiments, R ³ is H, D, C _1-6 alkyl, C _1-6 hydroxyalkyl or C _1-6 haloalkyl.

In some embodiments, R ⁴ is H, D, C _1-6 alkyl, C _1-6 hydroxyalkyl or C _1-6 haloalkyl.

In some embodiments, L is -O-, -O-methylene-, -O-ethylene-, -S- or -NH-.

In some embodiments, R5 is a C _6-10 aryl or a ^5-10 membered heteroaryl, where each of the C _6-10 aryl and the 5-10 membered heteroaryl is independently and Optionally, it may be substituted with one, ^two or three ^R6s , where R6 is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C. _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 cyanoalkyl or C _1-6 hydroxyalkyl.

In some embodiments, W is a condensed cyclyl, a crosslinked cyclyl or a spirocyclyl, where the condensed cyclyl, the crosslinked cyclyl or the spirocyclyl is independently selected from N, O or S, 0, 1, A saturated or partially unsaturated 6-12 membered cyclyl containing 2, 3 or 4 heteroatoms, where W is optionally D, oxo (= O), F, Cl. , Br, I, hydroxy, amino, nitro, cyano, -C (= O) OR, -C (= O) NR ^a R ^b , -C (= NR) NR ^a R ^b , -NH-C (= NR) ) NR ^a R ^b , -SO ₂ R, -SO ₂ NR ^a R ^b , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkyl Even if substituted with one, two, three, four or five substituents independently selected from amino, C _1-6 haloalkyl, C _1-6 cyanoalkyl and C _1-6 hydroxyalkyl. Often, R, ^{Ra and R b are} as defined herein.

In other embodiments, Het is a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, where each of the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl is independently and Optionally, H, D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, carboxy and- It may be substituted with C (= O) NH ₂ .

In other embodiments, Het is pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolysyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl. Pyrimidinyl, pyridadinyl or pyrazinyl, where pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolysyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, frills, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl. Each of pyridyl, pyrimidinyl, pyridadinyl and pyrazineyl independently and optionally H, D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, methoxy. , Ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, carboxy and may be substituted with -C (= O) NH ₂ .

In other embodiments, R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy or C _1-3 haloalkyl.

In other embodiments, R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl or trifluoro. It is ethyl.

In other embodiments, R is H, D, C _1-3 alkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl.

In other embodiments, R is H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, cyclohexyl, cyclopentyl or cyclohexyl.

In other embodiments, ^Ra is H, D, C _1-3 alkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl.

In other embodiments, ^Ra is H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, cyclohexyl, cyclopentyl or cyclohexyl.

In other embodiments, R ^b is H, D, C _1-3 alkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl.

In other embodiments, ^Rb is H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, cyclohexyl, cyclopentyl or cyclohexyl.

In other embodiments, Ra and R ^b form ^a 3- to 6-membered heterocyclyl together with the N atom to which they are attached, where the 3- to 6-membered heterocyclyl is optionally oxo. It may be substituted with (= O), D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl.

によって表されるヘテロシクリル基から選択されるヘテロシクリルを形成し、
ここで、式（ｉ－ａ）から（ｉ－ｋ）によって表されるヘテロシクリル基は、任意に、オキソ（＝Ｏ）、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、メチル、エチル、イソプロピル、メトキシ、エトキシ、トリフルオロメチル、ジフルオロメチル又はトリフルオロエチルで置換されていてもよい。 In other embodiments, Ra and R ^b , together with the N atom to which they are attached, from formulas (Ia) to ( ^ik ) :.

Forming a heterocyclyl selected from the heterocyclyl groups represented by
Here, the heterocyclyl group represented by the formulas (ia) to (ik) is optionally oxo (= O), D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, It may be substituted with methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl or trifluoroethyl.

In other embodiments, R ³ is H, D, C _1-3 alkyl, C _1-3 hydroxyalkyl or C _1-3 haloalkyl.

In other embodiments, R ³ is H, D, methyl, ethyl, n-propyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or 2-fluoroethyl.

In some embodiments, ^R4 is H, D, C _1-3 alkyl, C _1-3 hydroxyalkyl or C _1-3 haloalkyl.

In other embodiments, ^R4 is H, D, methyl, ethyl, n-propyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or 2-fluoroethyl.

In other embodiments, R5 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl or a ^5-6 membered heteroaryl, where phenyl, naphthyl, 1,2,3,4- Each of the tetrahydronaphthyl and the ^5-6 membered heteroaryl may be independently and optionally substituted with one, two or three ^R6s , where R6 is H, D,. F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy, C _1-3 cyanoalkyl or C _{1 -3} hydroxyalkyl.

^In other embodiments, R5 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, frill, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl. Or pyridadinyl, where phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, frill, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl or pyridadinyl. Each of each may be independently and optionally substituted with one, ^two or three ^R6s , where R6 is H, D, F, Cl, Br, I, hydroxy, Amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, hydroxyethyl, cyanomethyl or cyanoethyl.

のうち１つを有し、
Ｘ^１、Ｘ^２及びＸ^３の各々は、独立に、結合、－ＣＨ_２－、－Ｏ－、－Ｓ－又は－ＮＨ－であり、
Ｙは、ＣＨ又はＮであり、
ｒ、ｓ、ｔ及びｎの各々は、独立に、０、１、２又は３であり、
各Ｗは、任意に、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、－Ｃ（＝Ｏ）ＯＨ、－Ｃ（＝Ｏ）ＮＨ_２、－Ｃ（＝ＮＨ）ＮＨ_２、－ＮＨ－Ｃ（＝ＮＨ）ＮＨ_２、－ＳＯ_２ＣＨ_３、－ＳＯ_２Ｃ_２Ｈ_５、Ｃ_１－３アルキル、Ｃ_３－６シクロアルキル、Ｃ_１－３アルコキシ、Ｃ_１－３ハロアルコキシ、Ｃ_１－３アルキルアミノ、Ｃ_１－３ハロアルキル、Ｃ_１－３シアノアルキル及びＣ_１－３ヒドロキシアルキルから独立に選択される１個、２個、３個、４個又は５個の置換基で置換されていてもよい。 In other embodiments, W has the following structure:

Have one of
Each of X ¹ , X ² and X ³ is independently bound, -CH _2- , -O-, -S- or -NH-.
Y is CH or N,
Each of r, s, t and n is 0, 1, 2 or 3 independently.
Each W is optionally D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, -C (= O) OH, -C (= O) NH ₂ , -C. (= NH) NH ₂ , -NH-C (= NH) NH ₂ , -SO ₂ CH ₃ , -SO ₂ C ₂ H ₅ , C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy , C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkyl, C _1-3 cyanoalkyl and C _1-3 hydroxyalkyl independently selected 1, 2, 3, 4 It may be substituted with 15 or 5 substituents.

のうち１つを有し、
各Ｗは、任意に、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、－Ｃ（＝Ｏ）ＯＨ、－Ｃ（＝Ｏ）ＮＨ_２、－Ｃ（＝ＮＨ）ＮＨ_２、－ＮＨ－Ｃ（＝ＮＨ）ＮＨ_２、－ＳＯ_２ＣＨ_３、－ＳＯ_２Ｃ_２Ｈ_５、メチル、エチル、イソプロピル、ｎ－ブチル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、トリフルオロメチル、ジフルオロメチル、メトキシ、エトキシ、イソプロポキシ、トリフルオロメトキシ、ジフルオロメトキシ、メチルアミノ、シアノメチル及びヒドロキシメチルから独立に選択される１個、２個、３個、４個又は５個の置換基で置換されていてもよい。 In some embodiments, W has the following structure:

Have one of
Each W is optionally D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, -C (= O) OH, -C (= O) NH ₂ , -C. (= NH) NH ₂ , -NH-C (= NH) NH ₂ , -SO ₂ CH ₃ , -SO ₂ C ₂ H ₅ , methyl, ethyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , 1, 2, 3, 4 or 5 independently selected from trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, methylamino, cyanomethyl and hydroxymethyl. It may be substituted with a substituent.

のうち１つを有する化合物又はその立体異性体、幾何異性体、互変異性体、Ｎ－オキシド、溶媒和物、水和物、代謝産物、エステル、薬学的に許容され得る塩若しくはプロドラッグが提供されるが、これらの化合物に限定されるものではない。 In some further embodiments, the following structures are described herein:

A compound having one of the following, a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvent, a hydrate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug. Provided, but not limited to these compounds.

In one aspect, the present specification refers to compounds of formula (I) or steric isomers, geometric isomers, metavariants, N-oxides, hydrates, solvates, metabolites, pharmaceuticals thereof. Provided are pharmaceutical compositions comprising acceptable salts or prodrugs, or pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles or combinations thereof.

In one aspect, the present specification provides the use of a compound of formula (I) or a pharmaceutical composition thereof in the manufacture of a pharmaceutical for preventing, treating or alleviating a disorder or disease controlled by ACC. Will be done.

In some embodiments, the disorder or disease controlled by acetyl-CoA carboxylase disclosed herein is a metabolic or neoplastic disorder.

In other embodiments, the disorders or diseases controlled by acetyl-CoA carboxylase disclosed herein include insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic steatohepatitis and Includes non-alcoholic steatohepatitis.

In other embodiments, the neoplastic disorders disclosed herein are breast cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell bronchial cancer. , Includes endometrial cancer, colorectal cancer and prostate cancer.

In another aspect, the invention prevents, treats, and treats ACC-controlled diseases in an affected body, including administering to the affected body a pharmaceutically acceptable and therapeutically effective amount of the compound. Concerning how to treat or alleviate.

In another aspect, the present specification provides a method of preparing, separating or purifying a compound of formula (I).

The pharmaceutical composition of the compound of the present invention, and the preparation, administration and use of the compound and the pharmaceutical composition, the characteristics of the pharmaceutical composition of the present invention are the compound represented by the formula (I), the compound listed in the present specification, and the compound. Includes pharmaceutically acceptable carriers, adjuvants, or excipients. The amount of the compound in the composition of the invention can effectively and detectably treat or reduce the disease controlled by ACC.

It will be appreciated that certain compounds disclosed herein may exist in free form for treatment or, where appropriate, as pharmaceutically acceptable derivatives thereof. As provided herein, some non-limiting examples of pharmaceutically acceptable derivatives are pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or the need. Directly or indirectly, administration to the affected entity comprises any other adduct or derivative capable of directly or indirectly providing the compounds described elsewhere herein, or metabolites or residues thereof.

As mentioned above, the pharmaceutically acceptable compositions disclosed herein further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, and when used herein, the compositions. Is suitable for any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonics, thickeners or emulsifiers, preservatives, suitable for the particular dosage form desired. , Solid binders, lubricants, etc. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick. and JC Boylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in the preparation of pharmaceutically acceptable compositions and known techniques for their manufacture. Any conventional carrier medium, for example by producing any undesired biological effect, or interacting with any other component of any pharmaceutically acceptable composition in a detrimental manner, etc. Its use is intended to be within the scope of the invention unless it is incompatible with the compounds of the invention.

The compounds of the invention can be combined as active ingredients with pharmaceutical carriers in compatible mixtures according to conventional drug formulation techniques. The carrier may take a wide variety of forms depending on the form of the preparation desired for administration, eg, oral or parenteral (including intravenous). In the preparation of compositions for oral dosage forms, any of the common pharmaceutical vehicles may be employed, for example in the case of oral liquid preparations of suspensions, elixirs and solutions, eg water, glycols. , Oils, alcohols, flavors, preservatives, colorants, etc .; or, for example, in the case of oral solid preparations of powders, hard or soft capsules and tablets, carriers such as starch, sugar, microcrystalline cellulose, diluents, etc. It is a granulating agent, a wetting agent, a binder, a disintegrant, and the like, and a solid oral preparation is preferable to a liquid preparation.

Tablets and capsules represent the most advantageous oral dosage unit form when solid pharmaceutical carriers are clearly employed due to their ease of administration. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent active compound. The proportion of active compound in these compositions can, of course, vary, but can conveniently be from about 2 percent to about 60 percent by weight of the unit. The amount of active compound in such a therapeutically effective composition is the amount at which an effective dose would be obtained. The active compound may be administered intranasally, for example as droplets or as a spray.

For tablets, pills, capsules and the like, the binder is, for example, gum tragant, acacia, cornstarch or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as cornstarch, potato starch, alginic acid; wetting agents, eg. , Magnesium stearate; and sweeteners such as sucrose, lactose or saccharin may also be included. When the dosage unit form is a capsule, it comprises a liquid carrier, eg, fatty oil, in addition to the above types of materials.

There may be various other materials for altering the physical form of the coating or dosage unit. For example, tablets can be coated with shellac, sugar or both. In addition to the active ingredient, the syrup or elixir agent may contain sucrose as a sweetener, methyl and propylparabens as preservatives, colorants and flavoring agents such as cherry or orange flavors.

It is contemplated that ophthalmic preparations, ointments for the eyes, powders, solutions and the like are also included in the scope of the present invention.

The compounds of the present invention can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water by being appropriately mixed with a surfactant, such as hydroxy-propyl cellulose. Dispersions may be prepared in mixtures in glycerol, liquid polyethylene glycols and oils thereof. Under general storage and specification conditions, these preparations contain preservatives to prevent the growth of microorganisms.

Suitable pharmaceutical forms for injectable applications include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the form needs to be sterile and fluid to the extent that easy injectability exists. It needs to be stable under manufacturing and storage conditions and also needs to be protected against the contaminant activity of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (eg, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Suitable routes of administration may be used to give effective doses of the compounds of the invention to mammals, especially humans. For example, oral, rectal, topical, parenteral, intraocular, intrapulmonary, intranasal and the like can be used. Dosage forms may include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably the compounds of the invention can be administered orally.

The therapeutically effective amount of a compound, pharmaceutical composition, or combination thereof depends on the species, weight, age and individual condition of the subject to be treated, the disorder or disease being treated or its severity. A normally skilled physician, clinician or veterinarian can easily determine the effect size of each active ingredient required to prevent, treat or inhibit progression of a disorder or disease.

When a compound of the invention treats or prevents an intended ACC controlled disease, the compound of the invention is administered at a daily dose of from about 0.1 milligrams to about 100 milligrams per kilogram of animal body weight, preferably. Is generally given a satisfactory effect when administered as a single daily dose, or in divided doses from 2 to 6 times daily, or as a sustained release form. For most large animals, the total daily dose is about 1.0 to about 1000 milligrams, preferably about 1 to about 50 milligrams. For a 70 kg adult, the total daily dose will generally range from about 7 milligrams to about 350 milligrams. This dosing regimen can be adjusted to provide the optimal therapeutic response.

Compounds, compositions or pharmaceutically acceptable salts or hydrates are diseases controlled by acetyl-CoA carboxylase, especially insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fats. It can effectively prevent, treat, treat or reduce sexual liver disease and non-alcoholic steatohepatitis.

General Synthetic Procedures In general, the compounds disclosed herein can be prepared by the methods described herein, and substituents are defined by formula (I) above, unless otherwise specified. That's right. The following non-limiting schemes and examples are provided to further illustrate the invention.

One of ordinary skill in the art can readily adapt the described chemical reactions to prepare many of the other compounds disclosed herein, and to prepare the compounds disclosed herein. It will be appreciated that alternative methods are considered to be within the scope disclosed herein. For example, the synthesis of compounds not exemplified in accordance with the present invention may be modified as apparent to those of skill in the art, eg, by appropriately protecting interfering groups, as well as other suitable known in the art other than those described. It can be successfully achieved by utilizing reagents and / or by making normal changes in reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing the other compounds disclosed herein.

In each of the examples described below, all temperatures are described in degrees Celsius unless otherwise stated. Reagents were purchased from commercial sources such as Aldrich Chemical Company, Arco Chemical Company, Alfa Chemical Company and J & K Scientific Ltd. and used without further purification unless otherwise stated. Common solvents are commercially available such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., Qingdao Ocean Chemical Factory. I bought it from the beginning.

Refluxing the solvent with sodium gave anhydrous THF, dioxane, toluene, and ether. Refluxing the solvent with CaH ₂ gave anhydrous CH ₂ Cl ₂ and CHCl ₃ . EtOAc, PE, hexane, DMAC and DMF were treated with anhydrous Na ₂ SO ₄ prior to use.

The reactions shown below are generally carried out under positive pressure of nitrogen or argon or in a dry tube in an anhydrous solvent (unless otherwise specified), and the reaction flask is typically introduced with the substrate and reagents by syringe. I attached a rubber flask for. Glassware was oven dried and / or heat dried. Glassware was oven dried and / or heat dried.

Column chromatography was performed using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. ^{1 1} H NMR spectra use CDCl ₃ , d6-DMSO, CD ₆ OD or d _{6 -} acetone (reported in ppm) as the solution and TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. Then, it was recorded at rt with a Bruker 400 MHz or 600 MHz spectrometer. When peak multiplicity is reported, the following abbreviations are used: s (single line), d (double line), t (triple line), m (multiple line), br (widening), dd ( Double line double line), q (quadruple line), dt (triple line double line), tt (triple line triple line), dddd (double line double line double line) Double line), qd (double line quadruple line), ddd (double line double line double line), td (double line triple line), dq (quadruple line double line) , Ddt (double line of triple line), tdd (triple line of double line of double line), dtd (double line of triple line of double line). Coupling constants, given, are reported in hertz (Hz).

Low resolution mass spectrum (MS) data was measured on an Agilent 6320 Series LC-MS spectrometer equipped with a G1312A binary pump and a G1316ATCC (column operated at 30 ° C.). The G1329A autosampler and G1315B DAD detector were applied for analysis and the ESI source was used in the LC-MS spectrometer.

Low resolution mass spectrum (MS) data was measured on an Agilent 6320 Series LC-MS spectrometer equipped with a G1311A binary pump and a G1316ATCC (column operated at 30 ° C.). The G1329A autosampler and G1315B DAD detector were applied for analysis and the ESI source was used in the LC-MS spectrometer.

Both LC-MS spectrometers were equipped with an Agilent Zorbax SB-C18, 2.1 x 30 mm, 5 μm column. The injection volume was determined by the sample concentration. The flow rate was 0.6 mL / min. HPLC peaks were recorded by UV-Vis wavelengths of 210 nm and 254 nm. The mobile phase was 0.1% formic acid (Phase A) in acetonitrile and 0.1% formic acid (Phase B) in ultrapure water. The gradient elution conditions are shown in Table 1.

化合物の純度は、Ａｇｉｌｅｎｔ １１００ Ｓｅｒｉｅｓ高速液体クロマトグラフィー（ＨＰＬＣ）、２１０ｎｍ及び２５４ｎｍにおけるＵＶ検出（Ｚｏｒｂａｘ ＳＢ－Ｃ１８、２．１×３０ｍｍ、４ミクロン、１０ｍｉｎ、０．６ｍＬ／ｍｉｎ流速、（Ｈ_２Ｏ中の０．１％ギ酸）中の５から９５％（ＣＨ_３ＣＮ中の０．１％ギ酸））で評価した。カラムは４０℃で操作した。

Compound purity is determined by Agilent 1100 Series High Performance Liquid Chromatography (HPLC), UV detection at 210 nm and 254 nm (Zorbax SB-C18, 2.1 × 30 mm, 4 microns, 10 min, 0.6 mL / min flow rate, (H ₂ O). It was evaluated at 5 to 95% (0.1% formic acid in CH ₃ CN) in 0.1% formic acid). The column was operated at 40 ° C.

The following abbreviations are used throughout this specification:
CDC1 ₃ chloroform-d
CD ₃ OD Methyl Alcohol-d4
DMF N, N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d ₆ dimethyl sulfoxide-d ₆
DCM dichloromethaneEA, EtOAc Ethyl acetate g Gram H ₂ O Water HCl Hydrogen chloride / Hydrochloric acid PE Petroleum ether Pd / C, Pd-C Palladium-Activated carbon mg Milliliter M mol / liter MeOH Methanol mol mol mmol mmol MPa Megapascal mL Milliliter NaOH Sodium hydroxide THF tetrahydrofuran TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl μL microliter.

Ｘは、限定されるものではないが、ハロ原子、メチルスルホニルオキシ、ｐ－メチルフェニルスルホニルオキシ等を含む脱離基であり、化合物Ｑは、化合物Ｍ及び化合物Ｐの光延反応により得られ得る。化合物（Ｉ）は、化合物Ｑのカップリング反応により得られ得る。

化合物Ｍ３は、適切な溶媒中で塩基の存在下、化合物Ｍ１、化合物Ｍ２及び硫黄華の環化反応によって得られ得る。塩基は、限定されるものではないが、モルホリンを含み、溶媒は、限定されるものではないが、エタノールを含む。 Schemes Typical synthetic procedures for preparing the disclosed compounds of the invention are shown in the following synthetic schemes. Unless otherwise specified, Het, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L and W are as defined herein.

X is a leaving group containing, but is not limited to, a halo atom, methylsulfonyloxy, p-methylphenylsulfonyloxy and the like, and compound Q can be obtained by the Mitsunobu reaction of compound M and compound P. Compound (I) can be obtained by a coupling reaction of compound Q.

Compound M3 can be obtained by a cyclization reaction of compound M1, compound M2 and sulfur flower in the presence of a base in a suitable solvent. The base contains, but is not limited to, morpholine, and the solvent includes, but is not limited to, ethanol.

Compound M5 can be obtained by reaction of compound M3, compound M4 and N, N'-carbonyldiimidazole in the presence of a base in a suitable solvent. The base comprises, but is not limited to, triethylamine and the solvent comprises, but is not limited to, DCM.

Compound M6 can be obtained by a condensation reaction of compound M5 in the presence of a base in a suitable solvent. The base comprises, but is not limited to, sodium ethoxide, and the solvent comprises, but is not limited to, ethanol.

Compound M7 can be obtained by hydrolysis of compound M6 in the presence of a base in a suitable solvent. The base includes, but is not limited to, sodium hydroxide, and the solvent includes, but is not limited to, a mixed solvent of methanol and water.

Compound M8 can be obtained by a decarbonization reaction of compound M7 and silver acetate in the presence of a base in a suitable solvent. The base comprises, but is not limited to, calcium carbonate, and the solvent comprises, but is not limited to, N-methylmorpholine.

化合物Ｐ２は、適切な溶媒中で触媒存在下、化合物Ｐ１及びＮ－ブロモスクシンイミドのフリーラジカル反応によって得られ得る。触媒は、限定されるものではないが、アゾジイソブチロニトリルを含み、溶媒は、限定されるものではないが、テトラクロロメタンを含む。 Compound M can be obtained by a halogenation reaction of compound M8 in a suitable solvent. The solvent includes, but is not limited to, methanol, glacial acetic acid and the like.

Compound P2 can be obtained by free radical reaction of compound P1 and N-bromosuccinimide in the presence of a catalyst in a suitable solvent. The catalyst comprises, but is not limited to, azodiisobutyronitrile and the solvent comprises, but is not limited to, tetrachloromethane.

Compound P4 can be obtained by a substitution reaction of compound P2 and compound P3 in the presence of a base in a suitable solvent. The base comprises, but is not limited to, sodium hydride, and the solvent comprises, but is not limited to, tetrahydrofuran.

Compound P can be obtained by a reduction reaction of compound P4 in the presence of a reducing agent in a suitable solvent. The reducing agent comprises, but is not limited to, lithium aluminum hydroxide, and the solvent comprises, but is not limited to, tetrahydrofuran.

工程１）５－アミノ－３－メチル－チオフェン－２，４－ジカルボン酸ジエチル
シアノ酢酸エチル（３０．００ｇ、２６０．０ｍｍｏｌ）、アセト酢酸エチル（３３．８３ｇ、２６０．０ｍｍｏｌ）及び硫黄華（８．３６ｇ、２６０．０ｍｍｏｌ）を無水エタノール（６０ｍＬ）にｒｔで溶解した。溶液を４５℃まで加熱し、次いで、モルホリン（３４．０ｍＬ、３９０ｍｍｏｌ）をゆっくりと滴下した。滴下の後、得られた混合物を６０℃まで加熱し、４時間撹拌した。反応を水（３６０ｍＬ）でクエンチし、混合物を撹拌しながらｒｔまで冷却した。多量の固体が沈殿した後、混合物を吸引濾過により濾過した。濾過ケークを３０％エタノール水溶液（１００ｍＬ）で洗浄し、真空乾燥して、標題化合物を黄色固体として得た（５４．１０ｇ、８０．９％）。 Example 1: 2- [1- [2-[[(3aS, 6aR) -5-hydroxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- Propionic acid

Step 1) 5-Amino-3-methyl-thiophene-2,4-dicarboxylic acid diethyl cyanoacetate (30.00 g, 260.0 mmol), ethyl acetoacetate (33.83 g, 260.0 mmol) and sulfur flower (8) .36 g, 260.0 mmol) was dissolved in absolute ethanol (60 mL) with rt. The solution was heated to 45 ° C. and then morpholine (34.0 mL, 390 mmol) was slowly added dropwise. After the dropping, the obtained mixture was heated to 60 ° C. and stirred for 4 hours. The reaction was quenched with water (360 mL) and the mixture was cooled to rt with stirring. After a large amount of solid had settled, the mixture was filtered by suction filtration. The filtered cake was washed with 30% aqueous ethanol solution (100 mL) and dried in vacuo to give the title compound as a yellow solid (54.10 g, 80.9%).

MS (ESI, pose.ion) m / z: 258.2 [M + H] ⁺ .

Step 2) 5-[(2-t-butoxy-1,1-dimethyl-2-oxa-ethyl) aminoformamide] -3-methyl-thiophene-2,4-dicarboxylic acid diethyl 5-amino-3-methyl- Diethyl thiophene-2,4-dicarboxylic acid (20.00 g, 77.73 mmol) was dissolved in DCM (160 mL) at rt, followed by triethylamine (43.2 mL, 311 mmol) and N, N'-carbonyldiimidazole (20.00 g, 77.73 mmol). 25.72 g) (155.4 mmol) was added. The mixture was stirred for 3 hours, then 2-amino-2-methyl-propionic acid t-butyl hydrochloride (16.30 g, 81.63 mmol) was added in portions. The resulting mixture was stirred for a further 5 hours. The reaction was quenched with water (300 mL). The resulting mixture was dispensed. The organic layer was washed with water (300 mL x 2), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was ground with PE and ethyl acetate (V / V = 15/1) to give the title compound as a pale yellow solid (29.10 g, 84.6%).

Step 3) 3- (2-t-butoxy-1,1-dimethyl-2-oxa-ethyl) -5-methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimidin-6-geic acid Ethyl 5-[(2-t-butoxy-1,1-dimethyl-2-oxa-ethyl) aminoformamide] -3-methyl-thiophene-2,4-dicarboxylic acid diethyl (58.00 g, 131.1 mmol) It was dissolved in absolute ethanol (550 mL) and then sodium ethoxide (36.41 g, 524.3 mmol) was added. The mixture was stirred at 80 ° C. overnight. The mixture was concentrated in vacuo. Water (600 mL) was added to the residue. The resulting mixture was adjusted to about pH 5 with dilute hydrochloric acid (2N). A large amount of solid was precipitated. The mixture was stirred for 30 minutes and filtered by suction filtration. The filtered cake was washed with water (100 mL) and dried in vacuo to give the title compound as a pale yellow solid (51.97 g, 100%). The product was used in the next step without further purification.

MS (ESI, neg.ion) m / z: 395.1 [MH] ^- .

Step 4) 3- (2-t-butoxy-1,1-dimethyl-2-oxa-ethyl) -5-methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimidin-6-formic acid 3- (2-t-butoxy-1,1-dimethyl-2-oxa-ethyl) -5-methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimidin-6-ethyl formate (51) .97 g, 131.1 mmol) dissolved in methanol (250 mL) and tetrahydrofuran (100 mL) at rt, followed by sodium hydroxide solution (21.40 g, 524.3 mmol) in water (120 mL) and tetrabutylammonium bromide. (4.23 g, 13.1 mmol) was added. The mixture was heated to 65 ° C. and stirred for 2.5 hours. The mixture was concentrated in vacuo. Water (600 mL) was added to the residue. The resulting mixture was adjusted to about pH 3 with dilute hydrochloric acid (2N). A large amount of solid was precipitated. The mixture was filtered by suction filtration. The filter cake was washed with water (100 mL) and vacuum dried to give the title compound as a gray solid (46.74 g, 96.8%).

MS (ESI, neg.ion) m / z: 367.1 [MH] ^- .

Step 5) 2-Methyl-2- (5-methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) -6-propionic acid t-butyl 3- (2-t) -Butoxy-1,1-dimethyl-2-oxa-ethyl) -5-methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimidin-6-formic acid (48.80 g, 132.5 mmol) Was dissolved in N-methylpyrrolidone (900 mL) at rt, and then potassium carbonate (22.00 g, 159.2 mmol) and silver acetate (27.07 g, 158.9 mmol) were added. The mixture was heated to 110 ° C. and stirred for 2 hours. The resulting mixture was cooled to rt and filtered by suction filtration. The filtrate was diluted with water (2 L). The resulting mixture was extracted with ethyl acetate (500 mL x 2). The combined organic layers were washed successively with saturated ammonium chloride solution (500 mL) and saturated hydrous NaCl (200 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was ground with PE and ethyl acetate (V / V = 10/1) to give the title compound as a gray solid (20.54 g, 47.8%).

MS (ESI, neg.ion) m / z: 323.1 [MH] ^- .

Step 6) 2- (6-bromo-5-methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) -2-methyl-propionic acid t-butyl 2-methyl- 2- (5-Methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) t-butyl propionic acid (20.54 g, 63.32 mmol) and sodium acetate trihydrate (18.96 g, 139.3 mmol) was dissolved in glacial acetic acid (300 mL), then bromine (3.57 mL, 69.7 mmol) was slowly added dropwise. After the dropping, the mixture was stirred at rt for 1 hour. The reaction was quenched with water (100 mL). A large amount of solid was precipitated. The mixture was filtered by suction filtration. The filter cake was dissolved in ethyl acetate (500 mL). The solution was washed successively with saturated sodium thiosulfate solution (100 mL) and saturated hydrous NaCl (200 mL), then dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was ground with PE and ethyl acetate (V / V = 10/1) to give the title compound as a white solid (25.00 g, 92.2%).

MS (ESI, pose.ion) m / z: 426.0 [M + Na] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ10.66 (s, 1H), 2.39 (s, 3H), 1.81 (s, 6H), 1.48 (s, 9H).

Step 7) (3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a, 4,6,6a-hexahydro-1H-pentalene]- (3aR, 6aS) -5', 5'-dimethylspiro [1,3,3a, 4,6,6a-hexahydropentalenyl-5,2'-1 in 2'-all anhydrous methanol (40 mL)) , 3-Dioxane] -2-one (24.50 g, 109.2 mmol) was added partly with sodium borohydride (5.78 g, 150.0 mmol) under N ₂ on an ice bath. The mixture was stirred on an ice bath for 2 hours. The mixture was quenched by dropping water (50 mL). The resulting mixture was extracted with ethyl acetate (120 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 4/1) to give the title compound as a colorless oil (18.00 g, 72.8%).

Step 8) 2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a, 4,6,6a-hexahydro-1H-" Pentalenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) acetic acid (3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane l-] in anhydrous tetrahydrofuran (20 mL) Sodium hydride (1.95 g, 48) in a solution of 2,5'-2,3,3a, 4,6,6a-hexahydro-1H-pentalene] -2'-ol (3.09 g, 13.7 mmol). .8 mmol) was added in portions under _N2 on an ice bath. After stirring on an ice bath for 15 minutes, a solution of 2-bromo-2- (methoxyphenyl) acetic acid (3.00 g, 12.2 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to the mixture. After the dropping, the mixture was transferred to rt and stirred for another 4 hours. The mixture was quenched by dropping water (30 mL) on an ice bath and the resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined aqueous layer was adjusted to pH about 3 with dilute hydrochloric acid (2N) and then extracted with ethyl acetate (30 mL × 2). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (2.20 g, 46.0%). The product was used in the next step without further purification.

Step 9) 2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a, 4,6,6a-hexahydro-1H-" Pentarenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) ethanol 2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-" in anhydrous tetrahydrofuran (20 mL) Dioxane-2,5'-2,3,3a, 4,6,6a-hexahydro-1H-pentarenyl] -2'-yl] oxy-2- (2-methoxyphenyl) acetic acid (2.20 g, 5.63 mmol) ), Lithium aluminum hydride (0.44 g, 11.0 mmol) was partially added on an ice bath. After the mixture was stable, the mixture was transferred to rt and stirred for 2 hours. The mixture was quenched by dropping water (0.44 mL) on an ice bath. Sodium hydroxide solution (0.44 mL, 15%) and water (1.32 mL) were then added to the mixture in sequence. The resulting mixture was stirred at rt for a further 15 minutes, anhydrous sodium sulfate was added and the mixture was stirred for a further 15 minutes. The mixture was filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 4/1) to give the title compound as a colorless oil (1.30 g, 61.3%).

MS (ESI, pose.ion) m / z: 399.3 [M + Na] ⁺ .

Step 10) 2- [1- [2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a,4,6 6a-Hexahydro-1H-pentalenyl] -2'-yl] oxy-2- (2-methoxyphenyl) ethyl] -6-bromo-5-methyl-2,4-dioxo-thieno [2,3-d] pyrimid -3-Il] -2-Methyl-propionic acid t-butyl 2- (6-bromo-5-methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) -2 -T-butyl methyl-propionate (1.45 g, 3.60 mmol), 2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2) , 3,3a, 4,6,6a-hexahydro-1H-pentalenyl] -2'-yl] oxy-2- (2-methoxyphenyl) ethanol (1.30 g, 3.45 mmol), triphenylphosphine (1. 80 g, 6.79 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) with rt. Diisopropyl azodicarboxylate (1.40 g, 6.79 mmol) was added to the mixture under N ₂ , and the resulting mixture was stirred at rt for 12 hours and concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 6/1) to give the title compound as a white solid (1.70 g, 64.6%).

Step 11) 2- [1- [2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a,4,6 6a-Hexahydro-1H-pentalenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3 -D] Pyrimid-3-yl] -2-methyl-propionic acid t-butyl 2- [1- [2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane] -2,5'-2,3,3a,4,6,6a-hexahydro-1H-pentalenyl] -2'-yl] oxy-2- (2-methoxyphenyl) ethyl] -6-bromo-5-methyl -2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionate t-butyl (1.70 g, 2.23 mmol) and 2-tributylstannyloxazole (4. 00 g (11.2 mmol) was dissolved in toluene (20 mL) under rt, _N2 , and then tetrakispalladium- (triphenylphosphine) (1.30 g, 1.12 mmol) was added. The mixture was stirred at 110 ° C. for 8 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 8/1) to give the title compound as a white solid (0.75 g). 45.0%).

Step 12) 2- [1- [2-[[(3aR, 6aS) -5-oxa-2,3,3a, 4,6,6a-hexahydro-1H-pentalenyl-2-yl] oxy] -2- (2-Methoxyphenyl) Ethyl] -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propaneic acid 2- [1- [2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3a,4,6,6a-hexahydro-1H] -Pentarenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido- 3-Il] -2-Methyl-propionic acid t-butyl (0.75 g, 1.0 mmol) was dissolved in DCM (10 mL) with rt, and then 2,2,2-trifluoroacetic acid (2 mL) was added. did. The mixture was stirred for 4 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 1/1) to give the title compound as a pale yellow solid (0). .500 g, 82.0%).

MS (ESI, pose.ion) m / z: 608.3 [M + H] ⁺ .

Step 13) 2- [1- [2-[[(3aS, 6aR) -5-hydroxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propane 2- [1- [2-[[(3aR, 6aS) -5-oxa-2,3,3a, 4,6,6a-hexahydro-1H-pentarenyl-2-yl] in anhydrous methanol (10 mL)] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl -Sodium borohydride (0.10 g, 2.6 mmol) was added partially to a solution of propanoic acid (0.500 g, 0.82 mmol) under N ₂ on an ice bath. The mixture was stirred at rt for 6 hours. The mixture was quenched by dropping water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 1/1) to give the title compound as a white solid (0.43 g, 86.0%).

MS (ESI, pose.ion) m / z: 632.2 [M + Na] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.72 (s, 1H), 7.54 (d, J = 6.4 Hz, 1H), 7.32 (t, J = 6.8 Hz, 1H), 7. 25 (s, 1H), 7.04 (t, J = 7.4Hz, 1H), 6.90 (d, J = 8.2Hz, 1H), 5.34-5.29 (m, 1H), 4.34-4.26 (m, 1H), 4.25-4.20 (m, 1H), 4.01-3.95 (m, 1H), 3.93 (s, 3H), 3. 84-3.80 (m, 1H), 2.86 (s, 3H), 2.33-2.25 (m, 2H), 2.06-1.92 (m, 4H), 1.89 ( s, 3H), 1.84 (s, 3H), 1.75-1.68 (m, 1H), 1.60-1.56 (m, 1H), 1.55-1.50 (m, 2H).

２－［１－［２－［［（３ａＳ，６ａＲ）－５－ヒドロキシ－１，２，３，３ａ，４，５，６，６ａ－オクタヒドロペンタレン－２－イル］オキシ］－２－フェニル－エチル］－５－メチル－６－オキサゾール－２－イル－２，４－ジオキソ－チエノ［２，３－ｄ］ピリミド－３－イル］－２－メチル－プロパン酸を２－ブロモ－２－フェニル酢酸（０．８００ｇ、３．７２ｍｍｏｌ）から例１に記載の方法に従って調製した。標題化合物を白色固体として得た（０．２２ｇ、９５．０％）。 Example 2: 2- [1- [2-[[(3aS, 6aR) -5-hydroxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2-Phenyl-ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid

2- [1- [2-[[(3aS, 6aR) -5-hydroxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- Phenyl-ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid 2-bromo-2 -Prepared from phenylacetic acid (0.800 g, 3.72 mmol) according to the method described in Example 1. The title compound was obtained as a white solid (0.22 g, 95.0%).

MS (ESI, pose.ion) m / z: 580.3 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.70 (d, J = 0.5 Hz, 1H), 7.47-7.44 (m, 2H), 7.43-7.37 (m, 2H), 7.36-7.31 (m, 1H), 7.22 (d, J = 0.6Hz, 1H), 4.98-4.92 (m, 1H), 4.15-4.05 (m) , 2H) 3.96-3.89 (m, 1H) 3.84-3.76 (m, 1H) 2.84 (s, 3H) 2.30-2.18 (m, 2H) ), 2.03-1.91 (m, 2H), 1.89 (s, 3H), 1.85 (s, 3H), 1.83-1.76 (m, 2H), 1.66- 1.59 (m, 1H), 1.58-1.51 (m, 1H), 1.39-1.31 (m, 2H).

工程１）２－（２－メトキシフェニル）－２－（６－オキサスピロ［３．３］ヘプタン－２－オキシ）酢酸
無水テトラヒドロフラン（２２ｍＬ）中の６－オキサスピロ［３．３］ヘプタン－２－オール（０．８６ｇ、７．５ｍｍｏｌ）の溶液に、水素化ナトリウム（１．１０ｇ、２７．５ｍｍｏｌ）を氷浴上でＮ_２下、一部ずつ添加した。３０分間氷浴上で撹拌した後、無水テトラヒドロフラン（５ｍＬ）中の２－ブロモ－２－（メトキシフェニル）酢酸（１．６８ｇ、６．８６ｍｍｏｌ）の溶液を混合物に滴下した。滴下の後、混合物をｒｔに移し、更に４時間撹拌した。混合物を水（３０ｍＬ）を氷浴上で滴下することによってクエンチし、得られた混合物を酢酸エチル（３０ｍＬ×２）で抽出した。併せた水層を希塩酸（１Ｎ）でｐＨ約３に調節し、次いで、イソプロピルエーテル（３０ｍＬ×２）で抽出した。併せた有機層を飽和塩水（３０ｍＬ）で洗浄し、無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮して、標題化合物を淡黄色の油として得た（１．９１ｇ、１００％）。生成物を更なる精製無しで次の工程に用いた。 Example 3: 2- [1- [2- (2-Methoxyphenyl) -2- (6-oxaspiro [3.3] heptane-2-oxy) ethyl] -5-methyl-6-oxazole-2-yl- 2,4-Dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid

Step 1) 2- (2-Methoxyphenyl) -2- (6-oxaspiro [3.3] heptane-2-oxy) acetate 6-oxaspiro [3.3] heptane-2-ol in anhydrous tetrahydrofuran (22 mL) Sodium hydride (1.10 g, 27.5 mmol) was added partially to the solution (0.86 g, 7.5 mmol) under N ₂ on an ice bath. After stirring on an ice bath for 30 minutes, a solution of 2-bromo-2- (methoxyphenyl) acetic acid (1.68 g, 6.86 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise to the mixture. After the dropping, the mixture was transferred to rt and stirred for another 4 hours. The mixture was quenched by dropping water (30 mL) on an ice bath and the resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined aqueous layer was adjusted to pH about 3 with dilute hydrochloric acid (1N) and then extracted with isopropyl ether (30 mL x 2). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (1.91 g, 100%). The product was used in the next step without further purification.

Step 2) 2- (2-Methoxyphenyl) -2- (6-oxaspiro [3.3] heptane-2-oxy) ethanol 2- (2-methoxyphenyl) -2- (6) in anhydrous tetrahydrofuran (30 mL) Lithium aluminum hydride (0.39 g, 10 mmol) was partially added to a solution of -oxaspiro [3.3] heptane-2-oxy) acetic acid (1.91 g, 6.86 mmol) on an ice bath. After the mixture was stable, the mixture was transferred to rt and stirred for 40 minutes. The mixture was quenched by dropping water (10 mL) on an ice bath. The resulting mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 1/1) to give the title compound as a colorless oil (0.700 g, 38.6%).

Step 3) 2- [6-bromo-1- [2- (2-methoxyphenyl) -2- (6-oxaspiro [3.3] heptane-2-oxy) ethyl] -5-methyl-2,4- Dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl 2- [6-bromo-5-methyl-2,4-dioxo-1H-thieno [2,3] -D] Pyrimid-3-yl] -2-methyl-propionic acid t-butyl (1.12 g, 2.78 mmol), 2- (2-methoxyphenyl) -2- (6-oxaspiro [3.3] heptane -2-Oxy) Ethanol (0.610 g, 2.31 mmol) and triphenylphosphine (1.24 g, 4.63 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL), and the air in the system was replaced with _N2 . Diisopropyl azodicarboxylate (0.95 mL, 4.7 mmol) was added dropwise to the mixture. The resulting mixture was stirred at rt for 22.5 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 8/1) to give the title compound as a white solid (1.05 g). , 70.0%).

Step 4) 2- [1- [2- (2-Methoxyphenyl) -2- (6-oxaspiro [3.3] heptane-2-oxy) ethyl] -5-methyl-6-oxazol-2-yl- 2,4-Dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl 2- [6-bromo-1- [2- (2-methoxyphenyl) -2) -(6-oxaspiro [3.3] heptane-2-oxy) ethyl] -5-methyl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid T-Butyl (1.05 g, 1.62 mmol) and 2-tributylstannyloxazole (1.16 g, 3.24 mmol) were dissolved in toluene (10 mL) under rt, _N2 , followed by tetrakispalladium- (tri). Phenylphosphine) (0.56 g, 0.48 mmol) was added. The mixture was stirred at 110 ° C. for 23.5 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 5/1) to give the title compound as a white solid (0.470 g). , 46.0%).

MS (ESI, pose.ion) m / z: 660.2 [M + Na] ⁺ .

Step 5) 2- [1- [2- (2-Methoxyphenyl) -2- (6-oxaspiro [3.3] heptane-2-oxy) ethyl] -5-methyl-6-oxazol-2-yl- 2,4-Dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid 2- [1- [2- (2-methoxyphenyl) -2- (6-oxaspiro [3-oxaspiro] .3] Heptane-2-oxy) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propion The acid t-butyl (0.270 g, 0.423 mmol) was dissolved in DCM (12 mL) at rt, followed by the addition of 2,2,2-trifluoroacetic acid (2 mL). The mixture was stirred for 3 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 3/1) to give the title compound as a white solid (0.050 g). 2,0.0%).

MS (ESI, pose.ion) m / z: 582.3 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.72 (s, 1H), 7.50-7.46 (m, 1H), 7.33-7.28 (m, 1H), 7.25 (s, 1H), 7.02 (t, J = 7.4Hz, 1H), 6.86 (d, J = 8.2Hz, 1H), 5.18-5.12 (m, 1H), 4.61- 4.51 (m, 4H), 4.21-4.12 (m, 1H), 4.12-4.03 (m, 1H), 3.86 (s, 3H), 3.77-3. 68 (m, 1H), 2.87 (s, 3H), 2.48-2.37 (m, 2H), 2.12-2.06 (m, 1H), 1.95-1.89 ( m, 1H), 1.87 (s, 3H), 1.84 (s, 3H).

工程１）（３Ｓ，６Ｓ）－６－［ｔ－ブチル（ジメチル）シリル］オキシ－２，３，３ａ，５，６，６ａ－ヘキサヒドロフロ［３，２－ｂ］フラン－３－オール
ＤＣＭ（２０ｍＬ）中の（３Ｓ，６Ｓ）－２，３，３ａ，５，６，６ａ－ヘキサヒドロフロ［３，２－ｂ］フラン－３，６－ジオール（４．００ｇ、２７．４ｍｍｏｌ）の溶液に、ｔ－ブチルジメチルシリルクロリド（４．６０ｇ、３０．５ｍｍｏｌ）をゆっくりとＮ_２下で添加し、次いで、イミダゾール（２．９０ｇ、４２．２ｍｍｏｌ）を添加した。混合物をｒｔで２２時間撹拌した。混合物を水（１００ｍＬ）を滴下することによってクエンチした。得られた混合物を酢酸エチル（１２０ｍＬ×２）で抽出した。併せた有機相を飽和塩水（５０ｍＬ）で洗浄し、無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮した。残分をシリカゲルクロマグラフィー（ＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ）＝５／１）で精製して、標題化合物を無色の油として得た（３．２０ｇ、４７．８％）。 Example 4: 2- [1- [2-[[(3S, 6S) -3-hydroxy-2,3,3a, 5,6,6a-hexahydroflo [3,2-b] hula-6-yl ] Oxy] -2-phenyl-ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid

Step 1) (3S, 6S) -6- [t-butyl (dimethyl) silyl] oxy-2,3,3a, 5,6,6a-hexahydroflo [3,2-b] furan-3-all DCM Of (3S, 6S) -2,3,3a, 5,6,6a-hexahydroflo [3,2-b] furan-3,6-diol (4.00 g, 27.4 mmol) in (20 mL) To the solution was slowly added t-butyldimethylsilyl chloride (4.60 g, 30.5 mmol) under _N2 , followed by imidazole (2.90 g, 42.2 mmol). The mixture was stirred at rt for 22 hours. The mixture was quenched by dropping water (100 mL). The resulting mixture was extracted with ethyl acetate (120 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 5/1) to give the title compound as a colorless oil (3.20 g, 47.8%).

Step 2) 2-[[(3S, 6S) -6- [t-butyl (dimethyl) silyl] oxy-2,3,3a, 5,6,6a-hexahydroflo [3,2-b] hula 3-Il] Oxy] -2-Phenyl-acetic acid (3S, 6S) -6- [t-butyl (dimethyl) silyl] Oxy-2,3,3a, 5,6,6a- in anhydrous tetrahydrofuran (25 mL) Sodium hydride (1.30 g, 30.7 mmol) in a solution of hexahydroflo [3,2-b] furan-3-ol (2.00 g, 7.68 mmol) in portions N ₂ on an ice bath. Added below. After stirring for 15 minutes, a solution of 2-bromo-2-phenylacetic acid (1.85 g, 8.45 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to the mixture. After the dropping, the mixture was transferred to rt and stirred for another 12 hours. The mixture was quenched by dropping water (20 mL) on an ice bath and the resulting mixture was washed with ethyl acetate (30 mL x 2). The combined aqueous layer was adjusted to pH about 5 with dilute hydrochloric acid (2N) and then extracted with ethyl acetate (50 mL × 2). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (1.80 g, 59.4%). The product was used in the next step without further purification.

MS (ESI, pose.ion) m / z: 417.2 [M + Na] ⁺ .

Step 3) 2-[[(3S, 6S) -6- [t-butyl (dimethyl) silyl] oxy-2,3,3a, 5,6,6a-hexahydroflo [3,2-b] hula 3-Il] Oxy] -2-Phenyl-ethanol 2-[[(3S, 6S) -6- [t-butyl (dimethyl) silyl] Oxy-2,3,3a, 5, in anhydrous tetrahydrofuran (20 mL) Lithium aluminum hydride (0.50 g, in a solution of 6,6a-hexahydroflo [3,2-b] Fra-3-yl] oxy] -2-phenyl-acetic acid (2.48 g, 6.29 mmol). 13.0 mmol) was added in portions on an ice bath. After the mixture was stable, the mixture was transferred to rt and stirred for 2 hours. The mixture was quenched by dropping water (0.50 mL) on an ice bath. Then, aqueous sodium hydroxide solution (0.50 mL, 15%) and water (1.50 mL) were added to the mixture in that order. The resulting mixture was stirred at rt for a further 15 minutes, anhydrous sodium sulfate was added and the mixture was stirred for a further 15 minutes. The mixture was filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 10/1) to give the title compound as a colorless oil (0.60 g, 25.0%).

MS (ESI, pose.ion) m / z: 403.1 [M + Na] ⁺ .

Step 4) 2- [6-bromo-1- [2-[[(3S, 6S) -6- [t-butyl (dimethyl) silyl] oxy-2,3,3a, 5,6,6a-hexahydro Flo [3,2-b] Fra-3-yl] Oxy] -2-phenyl-ethyl] -5-Methyl-2,4-dioxo-thieno [2,3-d] Pyrimid-3-yl] -2 -Methyl-propionic acid t-butyl 2- (6-bromo-5-methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) -2-methyl-propionic acid t- Butyl (0.58 g, 1.4 mmol), 2-[[(3S, 6S) -6- [t-butyl (dimethyl) silyl] oxy-2,3,3a, 5,6,6a-hexahydroflo [ 3,2-b] Fra-3-yl] oxy] -2-phenyl-ethanol (0.53 g, 1.4 mmol) and triphenylphosphine (0.75 g, 2.8 mmol) in anhydrous tetrahydrofuran (15 mL) rt. Dissolved in. Diisopropyl azodicarboxylate (0.56 g, 2.7 mmol) was added to the mixture under N ₂ , and the resulting mixture was stirred at rt for 12 hours and concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 6/1) to give the title compound as a white solid (0.71 g, 67.0%).

Step 5) 2- [1- [2-[[(3S, 6S) -6- [t-butyl (dimethyl) silyl] oxy-2,3,3a, 5,6,6a-hexahydroflo [3,] 2-b] Fra-3-yl] Oxy] -2-Phenyl-ethyl] -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] Pyrimid-3- Il] -2-methyl-propionic acid t-butyl 2- [6-bromo-1- [2-[[(3S, 6S) -6- [t-butyl (dimethyl) silyl] oxy-2,3,3a , 5,6,6a-Hexahydroflo [3,2-b] Fra-3-yl] Oxy] -2-phenyl-ethyl] -5-Methyl-2,4-dioxo-thieno [2,3-d ] Pyrid-3-yl] -2-methyl-propionic acid t-butyl (0.17 g, 0.22 mmol) and 2-tributylstannyloxazole (0.29 g, 0.67 mmol) in toluene (10 mL), rt, It was dissolved under _N2 and then tetraxpalladium- (triphenylphosphine) (0.12 g, 0.11 mmol) was added. The mixture was stirred at 110 ° C. for 12 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 6/1) to give the title compound as a white solid (0.10 g). , 60.0%).

MS (ESI, pose.ion) m / z: 777.2 [M + Na] ⁺ .

Step 6) 2- [1- [2-[[(3S, 6S) -3-hydroxy-2,3,3a, 5,6,6a-hexahydroflo [3,2-b] furan 6-yl]] Oxy] -2-phenyl-ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propaneic acid 2 -[1- [2-[[(3S, 6S) -6- [t-butyl (dimethyl) silyl] oxy-2,3,3a, 5,6,6a-hexahydroflo [3,2-b]] Fla-3-yl] oxy] -2-phenyl-ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2 -T-Butyl methyl-propionate (0.42 g, 0.56 mmol) was dissolved in DCM (8 mL) at rt, followed by the addition of 2,2,2-trifluoroacetic acid (4 mL). The mixture was stirred for 4 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 3/1) to give the title compound as a pale yellow solid (0). .22 g, 68.0%).

MS (ESI, pose.ion) m / z: 584.2 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.73 (s, 1H), 7.50-7.35 (m, 5H), 7.25 (s, 1H), 5.15-5.10 (m, 1H), 4.45 (t, J = 4.8Hz, 1H), 4.35 (t, J = 5.1Hz, 1H), 4.25 (d, J = 14.4Hz, 1H), 4. 18-4.11 (m, 1H), 4.04-3.96 (m, 1H), 3.95-3.87 (m, 1H), 3.86-3.82 (m, 1H), 3.82-3.77 (m, 1H), 3.47 (t, J = 8.2Hz, 1H), 3.04 (t, J = 8.4Hz, 1H), 2.87 (s, 3H) ), 1.90 (s, 3H), 1.87 (s, 3H).

２－［１－［２－［［（３Ｓ，６Ｓ）－３－ヒドロキシ－２，３，３ａ，５，６，６ａ－ヘキサヒドロフロ［３，２－ｂ］フラン６－イル］オキシ］－２－（２－メトキシフェニル）エチル］－５－メチル－６－オキサゾール－２－イル－２，４－ジオキソ－チエノ［２，３－ｄ］ピリミド－３－イル］－２－メチル－プロパン酸を２－ブロモ－２－（メトキシフェニル）酢酸（１．３５ｇ、５．５１ｍｍｏｌ）から例４に記載の方法に従って調製した。標題化合物を淡黄色の固体として得た（０．４５ｇ、７４．０％）。 Example 5: 2- [1- [2-[[(3S, 6S) -3-hydroxy-2,3,3a, 5,6,6a-hexahydroflo [3,2-b] furan 6-yl]] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl -Propionic acid

2- [1- [2-[[(3S, 6S) -3-hydroxy-2,3,3a, 5,6,6a-hexahydroflo [3,2-b] furan 6-yl] oxy]- 2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid Was prepared from 2-bromo-2- (methoxyphenyl) acetic acid (1.35 g, 5.51 mmol) according to the method described in Example 4. The title compound was obtained as a pale yellow solid (0.45 g, 74.0%).

MS (ESI, pose.ion) m / z: 636.1 [M + Na] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.72 (s, 1H), 7.52-7.45 (m, 1H), 7.37-7.31 (m, 1H), 7.25 (s, 1H), 7.04 (t, J = 7.5Hz, 1H), 6.93 (d, J = 8.2Hz, 1H), 5.55-5.46 (m, 1H), 4.45 ( t, J = 4.7Hz, 1H) 4.36 (t, J = 5.1Hz, 1H) 4.22-4.06 (m, 3H) 4.01-3.93 (m, 2H) ), 3.92 (s, 3H), 3.84-3.78 (m, 1H), 3.55 (t, J = 8.0Hz, 1H), 3.24 (t, J = 8.1Hz). , 1H), 2.87 (s, 3H), 1.88 (s, 3H), 1.87 (s, 3H).

工程１）（３ａＲ，６ａＳ）－５’，５’－ジメチルスピロ［１，３，３ａ，４，６，６ａ－ヘキサヒドロペンタレニル－５，２’－１，３－ジオキサン］－２－オン
１，３，３ａ，４，６，６ａ－ヘキサヒドロペンタレニル－２，５－ジオン（２０．００ｇ、１４４．８ｍｍｏｌ）及び２，２－ジメチルプロパン－１，３－ジオール（１６．００ｇ、１５３．６ｍｍｏｌ）をトルエン（１００．００ｍＬ）に溶解し、次いで、ｐ－トルエンスルホン酸（２．５０ｇ、１４．４ｍｍｏｌ）を添加した。混合物を１１５℃まで加熱し、一晩撹拌した。反応を停止し、混合物を真空濃縮して溶媒を除去し、残分をシリカゲルカラムクロマトグラフィー（ＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ）＝６／１）で精製して、標題化合物を白色固体として得た（１３．６０ｇ、４１．８９％）。 Example 6: 2- [1- [2-[[(3aR, 6aS) -5-oxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalenyl-2-yl] oxy] -2- (2-Methoxyphenyl) Ethyl] -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid

Step 1) (3aR, 6aS) -5', 5'-dimethylspiro [1,3,3a, 4,6,6a-hexahydropentarenyl-5,2'-1,3-dioxane] -2- On 1,3,3a, 4,6,6a-Hexahydropentalenyl-2,5-dione (20.00 g, 144.8 mmol) and 2,2-dimethylpropane-1,3-diol (16.00 g) , 153.6 mmol) was dissolved in toluene (100.00 mL), followed by the addition of p-toluenesulfonic acid (2.50 g, 14.4 mmol). The mixture was heated to 115 ° C. and stirred overnight. The reaction was stopped, the mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 6/1) to give the title compound as a white solid. (13.60 g, 41.89%).

Step 2) (3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a, 4,6,6a-hexahydro-1H-pentarenyl]- (3aR, 6aS) -5', 5'-dimethylspiro [1,3,3a, 4,6,6a-hexahydropentarenyl-5,2'-1 in 2'-all anhydrous methanol (40 mL)) , 3-Dioxane] -2-one (24.50 g, 109.2 mmol) was added with sodium borohydride (5.78 g, 150.0 mmol) in portions under N ₂ on an ice bath. The mixture was stirred for 2 hours. The mixture was quenched by dropping water (50 mL). The resulting mixture was extracted with ethyl acetate (120 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 4/1) to give the title compound as a colorless oil (18.00 g, 72.8%).

Step 3) 2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a, 4,6,6a-hexahydro-1H-" Pentarenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) acetic acid (3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2] in anhydrous tetrahydrofuran (20 mL) , 5'-2,3,3a, 4,6,6a-hexahydro-1H-pentarenyl] -2'-ol (3.09 g, 13.7 mmol) in a solution of sodium hydride (1.95 g, 48. 8 mmol) was added in portions on an ice bath under _N2 . After stirring for 15 minutes, a solution of 2-bromo-2- (methoxyphenyl) acetic acid (3.00 g, 12.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the mixture. After the addition, the mixture was transferred to rt and stirred for a further 4 hours. The mixture was quenched by dropping water (30 mL) on an ice bath and the resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined aqueous layer was adjusted to pH about 3 with dilute hydrochloric acid (2N) and then extracted with ethyl acetate (30 mL × 2). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (2.20 g, 46.0%).

Step 4) 2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a, 4,6,6a-hexahydro-1H-" Pentarenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) ethanol 2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-" in anhydrous tetrahydrofuran (20 mL) Dioxane-2,5'-2,3,3a, 4,6,6a-hexahydro-1H-pentarenyl] -2'-yl] oxy-2- (2-methoxyphenyl) acetic acid (2.20 g, 5.63 mmol) ), Lithium aluminum hydride (0.44 g, 11.0 mmol) was partially added on an ice bath. After the mixture was stable, the mixture was transferred to rt and stirred for 2 hours. Water (0.44 mL), aqueous sodium hydroxide solution (0.44 mL, 10%) and water (1.32 mL) were slowly added dropwise to the mixture on an ice bath in that order. The resulting mixture was stirred at rt for a further 15 minutes, anhydrous sodium sulfate was added and the mixture was stirred for a further 15 minutes. The mixture was filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 4/1) to give the title compound as a colorless oil (1.30 g, 61.3%).

MS (ESI, pose.ion) m / z: 399.3 [M + Na] ⁺ .

Step 5) 2- [1- [2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a, 4,6 6a-Hexahydro-1H-pentalenyl] -2'-yl] oxy-2- (2-methoxyphenyl) ethyl] -6-bromo-5-methyl-2,4-dioxo-thieno [2,3-d] pyrimid -3-Il] -2-Methyl-propionic acid t-butyl 2- (6-bromo-5-methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) -2 -T-Butyl methyl-propionate (1.45 g, 3.60 mmol) (prepared according to the method described in Step 6 of Example 1), 2-[(3'aR, 6'aS) -5,5-dimethyl Spiro [1,3-dioxane-2,5'-2,3,3a,4,6,6a-hexahydro-1H-pentalenyl] -2'-yl] oxy-2- (2-methoxyphenyl) ethanol (1) .30 g, 3.45 mmol) and triphenylphosphine (1.80 g, 6.79 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL) with rt. Diisopropyl azodicarboxylate (1.40 g, 6.79 mmol) was added to the mixture under N ₂ , and the resulting mixture was stirred at rt for 12 hours and concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 6/1) to give the title compound as a white solid (1.70 g, 64.6%).

Step 6) 2- [1- [2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a,4,6 6a-Hexahydro-1H-pentalenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3 -D] Pyrimid-3-yl] -2-methyl-propionic acid t-butyl 2- [1- [2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane] -2,5'-2,3,3a,4,6,6a-hexahydro-1H-pentalenyl] -2'-yl] oxy-2- (2-methoxyphenyl) ethyl] -6-bromo-5-methyl -2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionate t-butyl (1.70 g, 2.23 mmol) and 2-tributylstannyloxazole (4. 00 g (11.2 mmol) was dissolved in toluene (20 mL) at rt under N ₂ , and then tetrakispalladium- (triphenylphosphine) (1.30 g, 1.12 mmol) was added. The mixture was stirred at 110 ° C. for 8 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 8/1) to give the title compound as a white solid (0.75 g). 45.0%).

Step 7) 2- [1- [2-[[(3aR, 6aS) -5-oxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalenyl-2-yl] oxy] -2- (2-Methoxyphenyl) Ethyl] -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propaneic acid 2- [1- [2-[(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3a,4,6,6a-hexahydro-1H] -Pentarenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido- 3-Il] -2-Methyl-propionic acid t-butyl (0.75 g, 1.0 mmol) was dissolved in DCM (10 mL) with rt, and then 2,2,2-trifluoroacetic acid (2 mL) was added. did. The mixture was stirred for 4 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 1/1) to give the title compound as a pale yellow solid (0). .500 g, 82.0%).

MS (ESI, pose.ion) m / z: 608.3 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.71 (s, 1H), 7.49 (d, J = 6.9 Hz, 1H), 7.34-7.28 (m, 1H), 7.23 ( s, 1H), 7.05 (d, J = 7.1Hz, 1H), 6.85 (d, J = 7.7Hz, 1H), 5.31 (t, J = 5.5Hz, 1H), 4.18-4.03 (m, 2H), 3.96-3.90 (m, 1H), 3.82 (s, 3H), 2.86 (s, 3H), 2.70-2. 58 (m, 2H), 2.50-2.33 (m, 2H), 2.27-2.09 (m, 2H), 2.06-1.98 (m, 2H), 1.89 ( s, 3H), 1.84 (s, 3H), 1.64-1.52 (m, 2H).

工程１）（３ａＲ，６ａＳ）－３ａ，５’，５’，６ａ－テトラメチルスピロ［１，３，４，６－テトラヒドロペンタレニル－５，２’－１，３－ジオキサン］－２－オン
３ａ，６ａ－ジメチル－１，３，４，６－テトラヒドロペンタレニル－２，５－ジオン（３．００ｇ、１８．０ｍｍｏｌ）、２，２－ジメチルプロパン－１，３－ジオール（１．９０ｇ、１８．２ｍｍｏｌ）及びｐ－トルエンスルホン酸（０．４０ｇ、２．３ｍｍｏｌ）をトルエン（２０ｍＬ）にＮ_２下、溶解した。混合物を１１５℃まで加熱し、１２時間撹拌した。反応混合物を真空濃縮して溶媒を除去し、残分をシリカゲルカラムクロマトグラフィー（ＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ）＝６／１）で精製して、標題化合物を無色の油として得た（３．００ｇ、６５．９％）。 Example 7: 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-3a, 6a-dimethyl-1,2,3,4,5,6-hexahydropentarenyl-2-yl ] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl-2-methyl -Propanic acid

Step 1) (3aR, 6aS) -3a, 5', 5', 6a-tetramethylspiro [1,3,4,6-tetrahydropentalenyl-5,2'-1,3-dioxane] -2- On 3a, 6a-dimethyl-1,3,4,6-tetrahydropentalenyl-2,5-dione (3.00 g, 18.0 mmol), 2,2-dimethylpropane-1,3-diol (1. 90 g, 18.2 mmol) and p-toluenesulfonic acid (0.40 g, 2.3 mmol) were dissolved in toluene (20 mL) under _N2 . The mixture was heated to 115 ° C. and stirred for 12 hours. The reaction mixture was concentrated in vacuum to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 6/1) to give the title compound as a colorless oil (3. 00g, 65.9%).

Step 2) (3'aR, 6'aS) -3'a, 5,5,6'a-tetramethylspiro [1,3-dioxane-2,5'-2,3,4,6-tetrahydro- 1H-pentalene] -2'-all anhydrous methanol (15 mL) in (3aR, 6aS) -3a, 5', 5', 6a-tetramethylspiro [1,3,4,6-tetrahydropentarenyl-5] , 2'-1,3-dioxane] -2-one (3.00 g, 11.9 mmol) in a solution of sodium borohydride (0.60 g, 16.0 mmol) in portions N ₂ on an ice bath. Added below. The mixture was stirred for 2 hours. The mixture was quenched by dropping water (50 mL). The resulting mixture was extracted with ethyl acetate (120 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 2/1) to give the title compound as a colorless oil (2.26 g, 74.7%).

Step 3) 2-[(3'aS, 6'aR) -3'a, 5,5,6'a-tetramethylspiro [1,3-dioxane-2,5'-2,3,4,6 -Tetrahydro-1H-Pentarenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) acetate (3'aR, 6'aS) -3'a, 5, 5, 6 in anhydrous tetrahydrofuran (20 mL) In a solution of'a-tetramethylspiro [1,3-dioxane-2,5'-2,3,4,6-tetrahydro-1H-pentalene] -2'-ol (2.30 g, 9.04 mmol), Sodium hydride (1.20 g, 30.0 mmol, 60%) was added portionwise on an ice bath under _N2 . After stirring on an ice bath for 15 minutes, a solution of 2-bromo-2- (methoxyphenyl) acetic acid (1.80 g, 7.34 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the mixture. After the addition, the mixture was transferred to rt and stirred for a further 4 hours. The mixture was quenched by dropping water (30 mL) on an ice bath and the resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined aqueous layer was adjusted to pH about 3 with dilute hydrochloric acid (2N) and then extracted with ethyl acetate (30 mL × 2). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (1.60 g, 52.1%).

MS (ESI, pose.ion) m / z: 419.3 [M + H] ⁺ .

Step 4) 2-[(3'aS, 6'aR) -3'a, 5,5,6'a-tetramethylspiro [1,3-dioxane-2,5'-2,3,4,6 -Tetrahydro-1H-Pentarenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) ethanol 2-[(3'aS, 6'aR) -3'a, 5, in anhydrous tetrahydrofuran (20 mL) 5,6'a-Tetramethylspiro [1,3-dioxane-2,5'-2,3,4,6-tetrahydro-1H-pentarenyl] -2'-yl] oxy-2- (2-methoxyphenyl) ) Lithium aluminum hydride (0.45 g, 12.0 mmol) was partially added to a solution of acetic acid (1.90 g, 4.54 mmol) on an ice bath. After the mixture was stable, the mixture was transferred to rt and stirred for 2 hours. The mixture was quenched by dropping water (0.45 mL) on an ice bath. Then, aqueous sodium hydroxide solution (0.45 mL, 15%) and water (1.35 mL) were added to the mixture in that order. The resulting mixture was stirred at rt for a further 15 minutes, anhydrous sodium sulfate was added and the mixture was stirred for a further 15 minutes. The mixture was filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 6/1) to give the title compound as a colorless oil (0.55 g, 30.1%).

MS (ESI, pose.ion) m / z: 427.3 [M + Na] ⁺ .

Step 5) 2- [1- [2-[(3'aS, 6'aR) -3'a, 5,5,6'a-tetramethylspiro [1,3-dioxane-2,5'-2] , 3,4,6-Tetrahydro-1H-pentarenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) ethyl] -6-bromo-5-methyl-2,4-dioxo-thieno [2, 3-d] Pyrimid-3-yl] -2-methyl-propionic acid t-butyl 2- (6-bromo-5-methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimid-3 -Il) -2-methyl-propionic acid t-butyl (0.60 g, 1.5 mmol), 2-[(3'aS, 6'aR) -3'a, 5,5,6'a-tetramethyl Spiro [1,3-dioxane-2,5'-2,3,4,6-tetrahydro-1H-pentalenyl] -2'-yl] oxy-2- (2-methoxyphenyl) ethanol (0.54g, 1) .3 mmol) and triphenylphosphine (0.75 g, 2.8 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL) under rt, _N2 . Diisopropyl azodicarboxylate (0.56 g, 2.7 mmol) was added to the mixture under N ₂ and the resulting mixture was stirred at rt for 12 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 6/1) to give the title compound as a white solid (1.10 g). , 99.0%).

Step 6) 2- [1- [2-[(3'aS, 6'aR) -3'a, 5,5,6'a-tetramethylspiro [1,3-dioxane-2,5'-2] , 3,4,6-Tetrahydro-1H-pentalenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo- Thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl 2- [1- [2-[(3'aS, 6'aR) -3'a, 5,5 , 6'a-Tetramethylspiro [1,3-dioxane-2,5'-2,3,4,6-tetrahydro-1H-pentarenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) Ethyl] -6-bromo-5-methyl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl (1.10 g, 1.39 mmol) And 2-tributylstannyloxazole (1.50 g, 4.19 mmol) dissolved in toluene (20 mL) under rt, _N2 , followed by tetrakispalladium- (triphenylphosphine) (0.80 g, 0.69 mmol). Was added. The mixture was stirred at 110 ° C. for 12 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 8/1) to give the title compound as a white solid (0.61 g). , 56.0%).

Step 7) 2- [1- [2-[[(3aS, 6aR) -3a, 6a-dimethyl-5-oxa-2,3,4,6-tetrahydro-1H-pentalene-2-yl] oxy]- 2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid 2- [1- [2-[(3'aS, 6'aR) -3'a, 5,5,6'a-tetramethylspiro [1,3-dioxane-2,5'-2,3, 4,6-Tetrahydro-1H-pentalenyl] -2'-yl] Oxy-2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2] , 3-d] Pyrimid-3-yl] -2-methyl-propionic acid t-butyl (0.61 g, 0.78 mmol) was dissolved in DCM (15 mL) with rt, followed by 2,2,2-tri. Fluoroacetic acid (5 mL) was added. The mixture was stirred for 4 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 1/1) to give the title compound as a pale yellow solid (0). .36 g, 72.0%).

MS (ESI, pose.ion) m / z: 636.2 [M + H] ⁺ .

Step 8) 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-3a, 6a-dimethyl-1,2,3,4,5,6-hexahydropentalene-2-yl] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl -Proanoic acid 2- [1- [2-[[(3aS, 6aR) -3a, 6a-dimethyl-5-oxa-2,3,4,6-tetrahydro-1H-pentalene-" in anhydrous methanol (10 mL) 2-Il] Oxy] -2- (2-Methoxyphenyl) ethyl] -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] To a solution of -2-methyl-propaneic acid (0.36 g, 0.57 mmol), sodium boron hydride (0.08 g, 2.0 mmol) was added little by little on an ice bath under _N2 . The mixture was stirred at rt for 5 hours. The mixture was quenched by dropping water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 1/1) to give the title compound as a white solid (0.32 g, 89.0%).

MS (ESI, pose.ion) m / z: 638.3 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.72 (s, 1H), 7.52 (d, J = 6.7 Hz, 1H), 7.33-7.29 (m, 1H), 7.25 ( s, 1H), 7.03 (t, J = 7.4Hz, 1H), 6.87 (d, J = 8.2Hz, 1H), 5.29-5.22 (m, 1H), 4. 22-4.01 (s, 3H), 3.87 (s, 3H), 3.75-3.69 (m, 1H), 2.85 (s, 3H), 1.90 (s, 3H) 1.85 (s, 3H), 1.83-1.76 (m, 2H), 1.76-1.68 (m, 2H), 1.53-1.51 (m, 1H), 1 .43-1.35 (m, 3H), 0.98 (s, 3H), 0.96 (s, 3H).

工程１）２－［１－［２－［［（３ａＲ，６ａＳ）－５－オキサ－２，３，３ａ，４，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレニル－２－イル）オキシ］エチル］－５－メチル－６－オキサゾール－２－イル－２，４－ジオキソ－チエノ［２，３－ｄ］ピリミド－３－イル］－２－メチル－プロピオン酸ｔ－ブチル
２－［１－［２－［（３’ａＲ，６’ａＳ）－５，５－ジメチルスピロ［１，３－ジオキサン－２，５’－２，３，３ａ，４，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレニル］－２’－イル］オキシ－２－（２－メトキシフェニル）エチル］－５－メチル－６－オキサゾール－２－イル－２，４－ジオキソ－チエノ［２，３－ｄ］ピリミド－３－イル］－２－メチル－プロピオン酸ｔ－ブチル（３００ｍｇ、０．４０ｍｍｏｌ）（例６に従って調製した）をテトラヒドロフラン（１０ｍＬ）に溶解し、次いで、塩酸水溶液（６．０ｍＬ、２Ｎ）をｒｔで添加した。混合物を２４時間撹拌した。混合物に酢酸エチル（３０ｍＬ）を添加し、混合物を１０分間撹拌した。混合物を分配した後、水相を酢酸エチル（２０ｍＬ×２）で抽出した。併せた有機相を飽和含水ＮａＣｌで洗浄し、無水硫酸ナトリウム上で乾燥し、濾過した。濾液を真空濃縮して、標題化合物を淡黄色の油として得た（２６０ｍｇ、９７．９％）。 Example 8: 2- [1- [2-[[(3aR, 6aS) -5-amino-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl) oxy] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl 2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid Hydrochloride

Step 1) 2- [1- [2-[[(3aR, 6aS) -5-oxa-2,3,3a, 4,6,6a-hexahydro-1H-pentalenyl-2-yl) oxy] ethyl]- 5-Methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl 2- [1- [2- [2-] [(3'aR, 6'aS) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a,4,6,6a-hexahydro-1H-pentarenyl] -2' -Il] Oxy-2- (2-methoxyphenyl) ethyl] -5-Methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2 -T-Butyl methyl-propionate (300 mg, 0.40 mmol) (prepared according to Example 6) was dissolved in tetrahydrofuran (10 mL), followed by the addition of aqueous hydrochloric acid (6.0 mL, 2N) at rt. The mixture was stirred for 24 hours. Ethyl acetate (30 mL) was added to the mixture and the mixture was stirred for 10 minutes. After partitioning the mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (260 mg, 97.9%).

MS (ESI, pose.ion) m / z: 664.2 [M + H] ⁺ .

Step 2) 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl) oxy] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propion Acid t-butyl 2- [1- [2-[[(3aR, 6aS) -5-oxa-2,3,3a,4,6,6a-hexahydro-1H-pentarenyl-2-yl) oxy] ethyl] -5-Methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionate t-butyl (260 mg, 0.39 mmol) Was dissolved in ethyl acetate (10.0 mL) and the solution was cooled to 0 ° C. Then sodium borohydride (30 mg, 0.78 mmol) was added in portions. The mixture was stirred at 0 ° C. for 10 minutes and then at rt for 30 minutes. The mixture was cooled to 0 ° C. and quenched with saturated hydrous ammonium chloride (0.5 mL). Water (10 mL) and ethyl acetate (20 mL) were added to the mixture and the mixture was stirred for 10 minutes. After partitioning the mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a grayish white solid (246 mg, 94.3%).

Step 3) 2- [1- [2-[[(3aR, 6aS) -5-methylsulfonyloxy-1,2,3,3a,4,5,6,6a-octahydropentalene-2-yl] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl -T-Butyl propionate 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl ) Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2- T-Butyl methyl-propionate (240 mg, 0.36 mmol) was dissolved in DCM (5.0 mL), followed by the addition of triethylamine (0.1 mL, 0.70 mmol). The solution was cooled to 0 ° C. Then, methyl sulfonyl chloride (62 mg, 0.54 mmol) was added dropwise. The mixture was stirred at 0 ° C. for 1 hour. The mixture was quenched with water (5.0 mL) and the mixture was stirred for 10 minutes. After dispensing the mixture. The aqueous phase was extracted with DCM (10.0 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 7/3) to give the title compound as a grayish white solid (220 mg, 82.0%).

MS (ESI, pose.ion) m / z: 774.2 [M + H] ⁺ .

Step 4) 2- [1- [2-[[(3aR, 6aS) -5-azido-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propion Acid t-Butyl 2- [1- [2-[[(3aR, 6aS) -5-methylsulfonyloxy-1,2,3,3a,4,5,6,6a-octahydropentalene-2-yl ] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2- T-Butyl methyl-propionate (220 mg, 0.30 mmol) was dissolved in N, N-dimethylformamide (3.0 mL), followed by the addition of sodium azide (23 mg, 0.35 mmol). The mixture was stirred at 60 ° C. for 23 hours. The mixture was quenched with water (10 mL) and the mixture was stirred for 10 minutes. After dispensing the mixture. The aqueous phase was extracted with DCM (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 7/3) to give the title compound as a grayish white solid (200 mg, 97.9%).

Step 5) 2- [1- [2-[[(3aR, 6aS) -5-amino-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl) oxy] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propion Acid t-butyl 2- [1- [2-[[(3aR, 6aS) -5-azido-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- T-Butyl propionate (200 mg, 0.29 mmol) was dissolved in methanol (5.0 mL), followed by the addition of palladium carbon (20 mg, 0.19 mmol, 10%). The mixture was stirred at rt under H ₂ for 1.5 hours. The mixture was filtered and the filter cake was washed with methanol (20 mL). The filtrate was concentrated in vacuo to give the title compound as a grayish white solid (165 mg, 85.7%).

MS (ESI, pose.ion) m / z: 665.3 [M + H] ⁺ .

Step 6) 2- [1- [2-[[(3aR, 6aS) -5-amino-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl 2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid Hydrochloride 2- [1- [2-[[(3aR, 6aS) -5-amino-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl) oxy]- 2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl (165 mg, 0.25 mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (5.0 mL). The mixture was stirred at rt for 10 hours. The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound as a grayish white solid (7.0 mg, 4.4%).

MS (ESI, pose.ion) m / z: 609.2 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CD ₃ OD) δ7.98 (s, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.29 (d, J = 11.9 Hz, 2H), 7 .08-6.89 (m, 2H), 5.36-5.29 (m, 1H), 4.25-3.85 (m, 2H), 3.82 (s, 3H), 3.80 -3.72 (m, 1H), 3.56-3.43 (m, 1H), 2.79 (s, 3H), 2.65-2.50 (m, 2H), 1.95 (m) , 2H), 1.81 (s, 3H), 1.77 (s, 3H), 1.77-1.54 (m, 5H).

工程１）５－ヒドロキシ－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－シクロペンテノ［ｃ］ピロール－２－カルボン酸ｔ－ブチル
無水メタノール（１５ｍＬ）中の５－オキソ－１，３，３ａ，４，６，６ａ－ヘキサヒドロシクロペンテノ［ｃ］ピロール－２－カルボン酸ｔ－ブチル（２．５０ｇ、１１．１ｍｍｏｌ）の溶液に、水素化ホウ素ナトリウム（０．５６ｇ、１５．０ｍｍｏｌ）を一部ずつ氷浴上でＮ_２下、添加した。混合物を２時間撹拌した。混合物を水（５０ｍＬ）を滴下することによってクエンチした。得られた混合物を酢酸エチル（１２０ｍＬ×２）で抽出した。併せた有機相を飽和塩水（５０ｍＬ）で洗浄し、無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮した。残分をシリカゲルクロマグラフィー（ＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ）＝２／１）で精製して、標題化合物を無色の油として得た（２．５０ｇ、９９．１％）。 Example 9: 2- [1- [2- (1,2,3,3a, 4,5,6,6a-octahydrocyclopenteno [c] pyrrole-5-oxy) -2- (2-methoxyphenyl) ) Ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoate acid salt

Step 1) 5-Oxo-1,3 in 5-hydroxy-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-2-carboxylate t-butyl anhydrous methanol (15 mL) , 3a, 4,6,6a-hexahydrocyclopenteno [c] pyrrole-2-carboxylate t-butyl (2.50 g, 11.1 mmol) in a solution of sodium borohydride (0.56 g, 15. 0 mmol) was added little by little on an ice bath under _N2 . The mixture was stirred for 2 hours. The mixture was quenched by dropping water (50 mL). The resulting mixture was extracted with ethyl acetate (120 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 2/1) to give the title compound as a colorless oil (2.50 g, 99.1%).

Step 2) 2-[(2-t-Butyloxycarboryl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5-yl) oxy] -2- (2-) Methoxyphenyl) acetic acid t-butyl 5-hydroxy-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-2-carboxylate (2.50 g, 11) in anhydrous tetrahydrofuran (20 mL) Sodium hydride (1.00 g, 25.0 mmol, 60%) was added portionwise to a solution of (0.0 mmol) on an ice bath under _N2 . After stirring for 15 minutes, a solution of 2-bromo-2- (methoxyphenyl) acetic acid (2.00 g, 8.16 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the mixture. After the addition, the mixture was transferred to rt and stirred for a further 4 hours. The mixture was quenched by dropping water (30 mL) on an ice bath and the resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined aqueous layer was adjusted to pH about 5 with dilute hydrochloric acid (2N) and then extracted with ethyl acetate (30 mL × 2). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (2.80 g, 87.6%).

Step 3) 5- [2-Hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-2-carboxylate t-butyl 2-[(2-t-Butyloxycarboryl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5-yl) oxy] -2 in anhydrous tetrahydrofuran (20 mL) To a solution of-(2-methoxyphenyl) acetic acid (1.00 g, 2.55 mmol), lithium aluminum hydride (0.17 g, 4.3 mmol) was added in portions on an ice bath. After the mixture was stable, the mixture was transferred to rt and stirred for 2 hours. The mixture was quenched by dropping water (0.17 mL) on an ice bath. Sodium hydroxide solution (0.17 mL, 15%) and water (0.51 mL) were then added to the mixture in sequence. The resulting mixture was stirred at rt for a further 15 minutes, anhydrous sodium sulfate was added and the mixture was stirred for a further 15 minutes. The mixture was filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 6/1) to give the title compound as a colorless oil (0.32 g, 33.1%).

MS (ESI, pose.ion) m / z: 400.3 [M + Na] ⁺ .

Step 4) 5- [2- [3- (2-t-Butoxy-1,1-dimethyl-2-oxo-ethyl) -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-1-yl] -1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-2-carboxylic acid Acid t-Butyl 2- (6-bromo-5-methyl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) -2-methyl-propionate t-butyl (0. 95 g, 2.4 mmol), 5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-2-carboxylic acid The acid t-butyl (0.80 g, 2.1 mmol) and triphenylphosphine (1.10 g, 4.15 mmol) were dissolved in anhydrous tetrahydrofuran (25 mL) under _N2 with rt. Diisopropyl azodicarboxylate (0.90 g, 4.4 mmol) was added to the mixture under N ₂ , and the resulting mixture was stirred at rt for 12 hours and concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 6/1) to give the title compound as a white solid (0.78 g, 48.0%).

MS (ESI, pose.ion) m / z: 785.2 [M + Na] ⁺ .

Step 5) 5- [2- [3- (2-t-butoxy-1,1-dimethyl-2-oxo-ethyl) -6-oxazol-2-yl-2,4-dioxo-thieno [2,3] -D] Pyrimid-1-yl] -1- (2-Methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-2-carboxylate t-butyl 5- [2- [3- (2-t-Butoxy-1,1-dimethyl-2-oxo-ethyl) -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,] 3-d] Pyrimid-1-yl] -1- (2-Methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-2-carboxylic acid t- Butyl (0.78 g, 1.0 mmol) and 2-tributylstannyloxazole (1.10 g, 3.07 mmol) were dissolved in toluene (20 mL) under rt, _N2 , followed by tetrakispalladium- (triphenylphosphine). ) (0.60 g, 0.52 mmol) was added. The mixture was stirred at 110 ° C. for 12 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 6/1) to give the title compound as a white solid (0.31 g). 4,0.0%).

MS (ESI, pose.ion) m / z: 773.3 [M + Na] ⁺ .

Step 6) 2- [1- [2- (1,2,3,3a, 4,5,6,6a-octahydrocyclopenteno [c] pyrrole-5-oxy) -2- (2-methoxyphenyl) ) Ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoate acid salt 5- [2-] [3- (2-t-Butoxy-1,1-dimethyl-2-oxo-ethyl) -6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-1-yl ] -1- (2-Methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-2-carboxylate t-butyl (0.27 g, 1.0 mmol) ) Was dissolved in ethyl acetate (5 mL) at rt, and then a solution of HCl in EtOAc (5 mL) was added. The mixture was stirred at rt for 4 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 1/1) to give the title compound as a white solid (0.21 g). , 98.0%).

MS (ESI, pose.ion) m / z: 595.8 [M-HCl + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ10.34 (s, 1H), 7.72 (s, 1H), 7.39-7.33 (m, 2H), 7.22 (s, 1H), 7 .06-6.94 (m, 2H), 5.25 (m, 1H), 4.80 (m, 1H), 3.98 (s, 3H), 3.85 (m, 1H), 3. 78 (m, 1H), 3.59 (m, 1H), 3.45 (s, 1H), 2.94 (m, 2H), 2.85 (s, 3H), 1.96 (s, 3H) ), 1.85 (s, 3H), 1.77 (m, 2H), 1.60 (m, 1H), 1.28-1.22 (m, 3H).

工程１）５－ベンジルオキシ－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－シクロペンテノ［ｃ］ピロール－２－カルボン酸ｔ－ブチル
５－ヒドロキシ－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－シクロペンテノ［ｃ］ピロール－２－カルボン酸ｔ－ブチル（２．６０ｇ、１１．４ｍｍｏｌ）をテトラヒドロフラン（５０ｍＬ）に溶解した。溶液を０℃まで冷却し、水素化ナトリウム（０．６８６ｇ、１７．１５ｍｍｏｌ、６０％）を一部ずつ添加した。添加の後、混合物をｒｔに移し、３０分間撹拌し、次いで、臭化ベンジル（２．５４ｇ、１４．９ｍｍｏｌ）をゆっくりと添加した。混合物をｒｔで一晩撹拌した。混合物を氷水に注ぎ入れた。得られた混合物を酢酸エチル（３００ｍＬ×２）で抽出した。併せた有機相を飽和塩水で洗浄し、無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮した。残分をシリカゲルクロマグラフィー（ＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ）＝６／１）で精製して、標題化合物を黄色の油として得た（２．６３ｇ、７２．４％）。 Example 10: 2- [1- [2- (2-methoxyphenyl) -2-[(2-methylsulfonyl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5) -Il) Oxy] Ethyl] -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propaneic acid

Step 1) 5-benzyloxy-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-2-carboxylate t-butyl 5-hydroxy-3,3a, 4,5,6 , 6a-Hexahydro-1H-cyclopenteno [c] pyrrole-2-carboxylate t-butyl (2.60 g, 11.4 mmol) was dissolved in tetrahydrofuran (50 mL). The solution was cooled to 0 ° C. and sodium hydride (0.686 g, 17.15 mmol, 60%) was added in portions. After the addition, the mixture was transferred to rt, stirred for 30 minutes and then slowly added benzyl bromide (2.54 g, 14.9 mmol). The mixture was stirred at rt overnight. The mixture was poured into ice water. The resulting mixture was extracted with ethyl acetate (300 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 6/1) to give the title compound as a yellow oil (2.63 g, 72.4%).

MS (ESI, pose.ion) m / z: 340.5 [M + Na] ⁺ .

Step 2) 5-benzyloxy-1,2,3,3a, 4,5,6,6a-octahydrocyclopenteno [c] pyrrole hydrochloride 5-benzyloxy-3,3a, 4,5,6 6a-Hexahydro-1H-cyclopenteno [c] pyrrole-2-carboxylate t-butyl was dissolved in a solution of HCl in EtOAc (15 mL). The mixture was stirred for 1 hour. The mixture was filtered. The filter cake was washed with EtOAc (3 mL x 3) and dried in vacuo to give the title compound as a yellow solid (1.20 g, 100%). This crude product was used in the next step without further purification.

MS (ESI, pose.ion) m / z: 218.4 [M + H] ⁺ .

Step 3) 5-benzyloxy-2-methylsulfonyl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole 5-benzyloxy-1,2,3,3a,4,5 , 6,6a-Octahydrocyclopenteno [c] pyrrole hydrochloride (1.52 g, 6.99 mmol) was dissolved in DCM (30 mL), then triethylamine (2.95 mL, 0.70 mmol) was added. The solution was cooled to 0 ° C. Then, methyl sulfonyl chloride (1.20 g, 10.49 mmol) was added dropwise. The mixture was stirred at rt for 2.5 hours. The mixture was quenched with water (10 mL) and the mixture was stirred for 10 minutes. After dispensing the mixture. The aqueous phase was extracted with DCM (20 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 3/1) to give the title compound as a grayish white solid (1.76 g, 85.2%).

MS (ESI, pose.ion) m / z: 296.3 [M + H] ⁺ .

Step 4) 2-Methylsulfonyl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5-ol 5-benzyloxy-2-methylsulfonyl-3,3a, 4,5 , 6,6a-Hexahydro-1H-cyclopenteno [c] pyrrole (1.76 g, 5.96 mmol) was dissolved in methanol (50 mL), followed by palladium hydroxide (176 mg, 1.25 mmol) and glacial acetic acid (2. 0 mL) was added. The system was replaced with hydrogen gas three times and the mixture was stirred at rt under a hydrogen pressure of 4.0 MPa for 24 hours. The mixture was filtered. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (1.16 g, 94.8%).

MS (ESI, pose.ion) m / z: 206.1 [M + H] ⁺ .

Step 5) 2- (2-Methoxyphenyl) -2-[(2-methylsulfonyl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5-yl) oxy] acetic acid 2-Methylsulfonyl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5-ol (1.16 g, 5.65 mmol) was dissolved in tetrahydrofuran (50 mL). The mixture was cooled to 0 ° C. under _N2 and sodium hydride (678 mg, 16.95 mmol, 60%) was added. The mixture was stirred for 10 minutes and then at rt for 30 minutes, then 2-bromo-2- (2-fluorophenyl) acetic acid (1.52 g, 6.22 mmol) was added. The resulting mixture was stirred at rt for 18 hours. The mixture was poured into ice water (50 g) to quench the reaction, then ethyl acetate (50 mL) was added. The mixture was stirred for 10 minutes. After partitioning the mixture, the aqueous phase was adjusted to pH about 2 with dilute hydrochloric acid (1N) and extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (1.96 g, 93.9%).

MS (ESI, pose.ion) m / z: 370.2 [M + H] ⁺ .

Step 6) 2- (2-Methoxyphenyl) -2-[(2-Methylsulfonyl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5-yl) oxy] ethanol 2- (2-Methoxyphenyl) -2-[(2-Methylsulfonyl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5-yl) oxy] acetic acid (1. 96 g (5.31 mmol) was dissolved in tetrahydrofuran (50 mL). The mixture was cooled to −5 ° C. under N ₂ and lithium aluminum hydride (0.519 g, 13.26 mmol) was added in portions. The mixture was stirred for 2 hours. Water (0.3 mL), aqueous sodium hydroxide solution (0.3 mL, 10%) and water (1.0 mL) were slowly added dropwise to the mixture. Then anhydrous sodium sulfate was added and the resulting mixture was stirred at rt for 30 minutes. The mixture was filtered. The filter cake was washed with EtOAc (10 mL x 4). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 4/1) to give the title compound as a pale yellow oil (0.340 g, 18.0%).

MS (ESI, pose.ion) m / z: 378.2 [M + Na] ⁺ .

Step 7) 2- [1- [2- (2-Methoxyphenyl) -2-[(2-Methylsulfonyl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5) -Il) Oxy] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionate t-butyl (diphenyl) ) Cyril 2- (2-methoxyphenyl) -2-[(2-methylsulfonyl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5-yl) oxy] ethanol ( 130 mg, 0.36 mmol), diisopropyl azodicarboxylate (143 mg, 0.69 mmol) and 2-methyl-2- (5-methyl-6-oxazole-2-yl-2,4-dioxo-1H-thieno [2,] 3-d] Pyrimido-3-yl) -t-butyl (diphenyl) silyl (200 mg, 0.34 mmol) -propionate was dissolved in tetrahydrofuran (10.0 mL). Triphenylphosphine (184 mg, 0.69 mmol) was added to the mixture in portions under _N2 . The mixture was stirred at rt for 13 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 15/1) to give the title compound as a grayish white solid (300 mg, 94.4%).

Step 8) 2- [1- [2- (2-Methoxyphenyl) -2-[(2-Methylsulfonyl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5) -Il) Oxy] Ethyl] -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propaneic acid 2- [ 1- [2- (2-Methoxyphenyl) -2-[(2-Methylsulfonyl-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] pyrrole-5-yl) oxy]- 5-Methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionate t-butyl (diphenyl) silyl (300 mg, 0) .33 mmol) was dissolved in tetrahydrofuran (2.0 mL). A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mol / L, 0.45 mL, 0.45 mmol) was added to the mixture. The mixture was stirred at rt for 20 minutes. The mixture was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound as a grayish white solid (51 mg, 23.0%).

MS (ESI, pose.ion) m / z: 673.1 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.71 (d, J = 16.2 Hz, 1H), 7.47-7.28 (m, 2H), 7.04-6.94 (m, 1H), 6.90-6.85 (m, 1H), 4.58-4.55 (m, 1H), 3.92-3.86 (m, 3H), 3.85 (s, 3H), 3. 38-3.29 (m, 2H), 3.25-3.18 (m, 2H), 2.95-2.91 (m, 3H), 2.90-2.61 (m, 3H), 2.59-2.55 (m, 2H), 2.24-1.98 (m, 2H), 1.91 (s, 3H), 1.81 (s, 3H), 1.69-1. 52 (m, 2H).

工程１）２－ヒドロキシ－６－アザスピロ［３．３］ヘプタン－６－カルボン酸ｔ－ブチル
２－オキソ－６－アザスピロ［３．３］ヘプタン－６－カルボン酸ｔ－ブチル（２．００ｇ、９．４７ｍｍｏｌ）をＥｔＯＡｃ（４０ｍＬ）に溶解した。混合物を０℃まで冷却し、水素化ホウ素ナトリウム（５４８ｍｇ、１４．１９ｍｍｏｌ）を一部ずつ添加し、混合物を１０分間０℃で撹拌し、次いで、更にｒｔで３０分間撹拌した。混合物を０℃まで冷却し、飽和含水塩化アンモニウム（２．０ｍＬ）でクエンチした。混合物を３０分間撹拌し、水（２０ｍＬ）及び酢酸エチル（５０ｍＬ）を添加し、混合物を１０分間撹拌した。混合物を分配した後、水相を酢酸エチル（１００ｍＬ×２）で抽出した。併せた有機相を飽和含水ＮａＣｌで洗浄し、無水硫酸ナトリウム上で乾燥し、濾過した。濾液を真空濃縮して、標題化合物を灰白色の固体として得た（１．８０ｇ、８９．２％）。 Example 11: 2- [1- [2- (6-azaspiro [3.3] heptane-2-oxy-2- (2-methoxyphenyl) ethyl) -5-methyl-6-oxazole-2-yl-2) , 4-Dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanthate

Step 1) 2-Hydroxy-6-azaspiro [3.3] heptane-6-carboxylate t-butyl 2-oxo-6-azaspiro [3.3] heptane-6-carboxylate t-butyl (2.00 g, 9.47 mmol) was dissolved in EtOAc (40 mL). The mixture was cooled to 0 ° C., sodium borohydride (548 mg, 14.19 mmol) was added in portions, the mixture was stirred at 0 ° C. for 10 minutes and then further stirred at rt for 30 minutes. The mixture was cooled to 0 ° C. and quenched with saturated hydrated ammonium chloride (2.0 mL). The mixture was stirred for 30 minutes, water (20 mL) and ethyl acetate (50 mL) were added and the mixture was stirred for 10 minutes. After partitioning the mixture, the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a grayish white solid (1.80 g, 89.2%).

MS (ESI, pose.ion) m / z: 236.1 [M + H] ⁺ .

Step 2) 2-[(6-t-Butoxycarbonyl-6-azaspiro [3.3] heptane-2-yl) oxy] -2- (2-methoxyphenyl) acetate 2-hydroxy-6-azaspiro [3. 3] T-butyl heptane-6-carboxylate (1.80 g, 8.44 mmol) was dissolved in tetrahydrofuran (40 mL). The mixture was cooled to 0 ° C. under N ₂ and sodium hydride (1.01 g, 25.3 mmol, 60%) was added. The mixture was stirred for 10 minutes and then at rt for 30 minutes, then 2-bromo-2- (2-methoxyphenyl) acetic acid (1.86 g, 7.59 mmol) was added. The resulting mixture was stirred at rt for 18 hours. The mixture was cooled to 0 ° C. and quenched with saturated hydrous ammonium chloride (0.5 mL). The mixture was stirred for 30 minutes, water (10 mL) and ethyl acetate (20 mL) were added and the mixture was stirred for 10 minutes. After partitioning the mixture, the aqueous phase was adjusted to pH about 3 with dilute hydrochloric acid (1N) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a red oil (2.9 g, 90.9%).

MS (ESI, pose.ion) m / z: 400.1 [M + Na] ⁺ .

Step 3) 2- [2-Hydroxy-1- (2-methoxyphenyl) ethoxy] -6-azaspiro [3.3] heptane-6-carboxylate t-butyl 2-[(6-t-butoxycarbonyl-6) -Azaspiro [3.3] heptane-2-yl) oxy] -2- (2-methoxyphenyl) acetic acid (1.00 g, 2.65 mmol) was dissolved in tetrahydrofuran (30 mL). The mixture was cooled to 0 ° C. under N ₂ and lithium aluminum hydride (207 mg, 5.29 mmol) was added in portions. The mixture was stirred for 2 hours. Water (0.3 mL), aqueous sodium hydroxide solution (0.3 mL, 10%) and water (1.0 mL) were slowly added dropwise to the mixture. The mixture was then stirred at rt, anhydrous sodium sulfate was added, and the resulting mixture was further stirred at rt for 30 minutes. The mixture was filtered. The filter cake was washed with EtOAc (10 mL x 4). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 7/3) to give the title compound as a grayish white solid (416 mg, 43.1%).

MS (ESI, pose.ion) m / z: 386.5 [M + Na] ⁺ .

Step 4) 2- [2- [3- [2-t-butyl (diphenyl) silyl] oxy-1,1-dimethyl-2-oxa-ethyl] -5-methyl-6-oxazole-2-yl-2 , 4-Dioxo-thieno [2,3-d] pyrimido-1-yl] -1- (2-methoxyphenyl) ethoxy] -6-azaspiro [3.3] heptane-6-carboxylate t-butyl 2- [2-Hydroxy-1- (2-methoxyphenyl) ethoxy] -6-azaspiro [3.3] heptane-6-carboxylate t-butyl (209 mg, 0.57 mmol), triphenylphosphine (278 mg, 1.05 mmol) ) And 2-Methyl-2- (5-methyl-6-oxazol-2-yl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) propionate t-butyl (diphenyl) ) Cyril (300 mg, 0.52 mmol) (prepared according to the method of compound 95.4 described in WO201101169A1) is added to tetrahydrofuran (6 mL) and diisopropyl azodicarboxylate (216 mg, 1.05 mmol) is added dropwise under _N2 . did. The mixture was stirred at rt for 15 hours and concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 79/1) to give the title compound as a grayish white solid (244 mg, 50.7%).

Step 5) 2- [1- [2- (6-azaspiro [3.3] heptane-2-oxy) -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl- 2,4-Dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoate acid salt 2- [2- [3- [2-t-butyl (diphenyl) silyl] oxy- 1,1-dimethyl-2-oxa-ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-1-yl] -1- (2) -Methoxyphenyl) ethoxy] -6-azaspiro [3.3] heptane-6-carboxylate t-butyl (244 mg, 1.0 mmol) was dissolved in a solution of HCl in EtOAc (5.0 mL). The mixture was stirred at rt for 1 hour. The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound as a grayish white solid (54 mg, 32.9%).

MS (ESI, pose.ion) m / z: 581.1 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CD ₃ OD) δ7.98 (s, 1H), 7.46-7.41 (m, 1H), 7.32-7.25 (m, 2H), 7.01 (t) , J = 7.4Hz, 1H), 6.94 (d, J = 8.2Hz, 1H), 5.21-5.15 (m, 1H), 4.11-4.06 (m, 1H) 4.05-4.02 (m, 1H), 3.95 (s, 2H), 3.92 (d, J = 2.5Hz, 2H), 3.86-3.80 (m, 4H) , 2.79 (s, 3H), 2.53-2.41 (m, 2H), 2.18-2.11 (m, 1H), 2.07-2.00 (m, 1H), 1 .80 (s, 3H), 1.77 (s, 3H).

工程１）２－（２－メトキシフェニル）－２－［（６－メチル－６－アザスピロ［３．３］ヘプタン－２－イル）オキシ］エタノール
２－［（６－ｔ－ブトキシカルボニル－６－アザスピロ［３．３］ヘプタン－２－イル）オキシ］－２－（２－メトキシフェニル）酢酸（８００ｍｇ、２．１２ｍｍｏｌ）（例１１の工程２に従って調製した）をテトラヒドロフラン（１０．０ｍＬ）に溶解した。混合物をＮ_２下で０℃まで冷却し、水素化アルミニウムリチウム（２４８ｍｇ、６．３４ｍｍｏｌ）を一部ずつ添加した。混合物を４０℃で３０分間撹拌した。混合物に、水（０．３ｍＬ）、水酸化ナトリウム水溶液（０．３ｍＬ、１０％）及び水（１．０ｍＬ）をゆっくりと順に滴下した。次いで、混合物をｒｔで撹拌し、無水硫酸ナトリウムを添加し、得られた混合物を更にｒｔで３０分間撹拌した。混合物を濾過した。濾過ケークをＥｔＯＡｃ（１０ｍＬ×４）で洗浄した。濾液を真空濃縮した。残分をシリカゲルクロマグラフィー（ＭｅＯＨ／ＤＣＭ（Ｖ／Ｖ）＝１／９）で精製して、標題化合物を淡黄色の油として得た（３３０ｍｇ、５６．１％）。 Example 12: 2- [1- [2- (2-methoxyphenyl) -2-[(6-methyl-6-azaspiro [3.3] heptane-2-yl) oxy] ethyl] -5-methyl-6 -Oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid

Step 1) 2- (2-Methoxyphenyl) -2-[(6-methyl-6-azaspiro [3.3] heptane-2-yl) oxy] ethanol 2-[(6-t-butoxycarbonyl-6-) Azaspir [3.3] heptane-2-yl) oxy] -2- (2-methoxyphenyl) acetic acid (800 mg, 2.12 mmol) (prepared according to step 2 of Example 11) was dissolved in tetrahydrofuran (10.0 mL). did. The mixture was cooled to 0 ° C. under N ₂ and lithium aluminum hydride (248 mg, 6.34 mmol) was added in portions. The mixture was stirred at 40 ° C. for 30 minutes. Water (0.3 mL), aqueous sodium hydroxide solution (0.3 mL, 10%) and water (1.0 mL) were slowly added dropwise to the mixture. The mixture was then stirred at rt, anhydrous sodium sulfate was added, and the resulting mixture was further stirred at rt for 30 minutes. The mixture was filtered. The filter cake was washed with EtOAc (10 mL x 4). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromography (MeOH / DCM (V / V) = 1/9) to give the title compound as a pale yellow oil (330 mg, 56.1%).

MS (ESI, pose.ion) m / z: 278.1 [M + H] ⁺ .

Step 2) 2- [1- [2- (2-Methoxyphenyl) -2-[(6-methyl-6-azaspiro [3.3] heptane-2-yl) oxy] ethyl] -5-methyl-6 -Oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl (diphenyl) silyl 2- (2-methoxyphenyl)- 2-[(6-Methyl-6-azaspiro [3.3] heptane-2-yl) oxy] ethanol (265 mg, 0.95 mmol), diisopropyl azodicarboxylate (260 mg, 1.74 mmol) and 2-methyl-2. -(5-Methyl-6-oxazole-2-yl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) -t-butyl (diphenyl) silyl propionate (500 mg, 0) .87 mmol) (prepared according to the method for preparing compound 95.4 described in WO201101169A1) was dissolved in tetrahydrofuran (20.0 mL). A solution of triphenylphosphine (462 mg, 1.74 mmol) in tetrahydrofuran (3.0 mL) was added dropwise to the mixture under _N2 . The mixture was stirred at rt for 4 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with (methanol / dichloromethane (V / V) = 1/9) to give the title compound as an off-white solid (500 mg, 68.8%).

MS (ESI, pose.ion) m / z: 595.1 [M-TBDPS + H] ⁺ .

Step 3) 2- [1- [2- (2-Methoxyphenyl) -2-[(6-methyl-6-azaspiro [3.3] heptane-2-yl) oxy] ethyl] -5-methyl-6 -Oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid 2- [1- [2- (2-methoxyphenyl) -2) -[(6-Methyl-6-azaspiro [3.3] heptane-2-yl) oxy] ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3- d] Pyrimid-3-yl] -2-methyl-propionic acid t-butyl (diphenyl) silyl (500 mg, 0.60 mmol) was dissolved in tetrahydrofuran (10.0 mL). A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mmol / L, 3.6 mL, 3.60 mmol) added to the mixture. The mixture was stirred at rt for 3 hours. The mixture was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound as a grayish white solid (120 mg, 33.6%).

MS (ESI, pose.ion) m / z: 595.1 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ8.22 (s, 1H), 7.44-7.34 (m, 2H), 7.32-7.25 (m, 1H), 7.30- 6.96 (m, 2H), 5.08-4.96 (m, 1H), 4.12-4.03 (m, 1H), 4.02-3.92 (m, 1H), 3. 77 (s, 3H), 3.75-3.70 (m, 1H), 3.69-3.66 (m, 2H), 3.65-3.60 (m, 2H), 2.74 ( s, 3H), 2.51 (s, 3H), 2.35-2.29 (m, 2H), 1.95-1.91 (m, 1H), 1.83-1.78 (m, 1H), 1.67 (s, 3H), 1.64 (s, 3H).

工程１）４－オキソシクロペンタン－１，２－ジカルボン酸ジメチル
メタノール（１５０ｍＬ）中の４－オキソシクロペンタン－１，２－ジカルボン酸（２０．００ｇ、５８．０９ｍｍｏｌ）の溶液に、塩化チオニル（２５．３ｍＬ、３４９ｍｍｏｌ）をｒｔで滴下した。混合物を６６℃で２時間撹拌した。混合物をｒｔまで冷却し水（２００ｍＬ）でクエンチした。得られた混合物をＥｔＯＡｃ（３００ｍＬ）で抽出した。有機層を飽和重炭酸ナトリウム溶液（１００ｍＬ）及び塩化ナトリウム溶液（１００ｍＬ）で順に洗浄し、無水硫酸ナトリウム上で乾燥し、真空濃縮して、標題化合物を白色の固体として得た（２３．２６ｇ、１００％）。 Example 13: 2- [2- [2- (3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] furan 5-oxy) -2- (2-methoxyphenyl) ethyl) -5 -Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid

Step 1) Thionyl chloride (20.00 g, 58.09 mmol) in a solution of 4-oxocyclopentane-1,2-dicarboxylic acid (20.00 g, 58.09 mmol) in dimethyl methanol (150 mL) 4-oxocyclopentane-1,2-dicarboxylic acid (150 mL). 25.3 mL, 349 mmol) was added dropwise by rt. The mixture was stirred at 66 ° C. for 2 hours. The mixture was cooled to rt and quenched with water (200 mL). The resulting mixture was extracted with EtOAc (300 mL). The organic layer was washed successively with saturated sodium bicarbonate solution (100 mL) and sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a white solid (23.26 g, 100%).

Step 2) Hydrogenate in a solution of dimethyl 4-oxocyclopentane-1,2-dicarboxylic acid (10.00 g, 49.95 mmol) in dimethyl 4-hydroxycyclopentane-1,2-dicarboxylic acid (50 mL). Sodium borohydride (2.32 g, 60.1 mmol) was added at −5 ° C. After the addition, the mixture was stirred for 2 hours. The mixture was quenched with saturated ammonium chloride solution (10 mL). Then anhydrous sodium sulfate (10 g) was added and the resulting mixture was stirred for 10 minutes. The mixture was filtered by suction filtration. The filter cake was washed with EtOAc (10 mL x 2). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 1/1) to give the title compound as a colorless oil (6.14 g, 60.77%).

Step 3) Dimethyl 4-benzyloxycyclopentane-1,2-dicarboxylic acid Dimethyl 4-hydroxycyclopentane-1,2-dicarboxylic acid in anhydrous N, N-dimethylformamide (60 mL) (6.13 g, 30.3 mmol) ), Sodium hydride (1.82 g, 45.5 mmol, 60%) was added in portions on an ice bath. The mixture was stirred at rt for 30 minutes, then benzyl bromide (7.2 mL, 61 mmol) was slowly added dropwise. After the dropping, the mixture was stirred at rt for 2 hours. The mixture was quenched by dropping water (40 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 6/1) to give the title compound as a pale yellow oil (3.84 g, 43.3%).

MS (ESI, pose.ion) m / z: 293.2 [M + H] ⁺ .

Step 4) [4-benzyloxy-2- (Hydroxymethyl) cyclopentyl] A solution of dimethyl 4-benzyloxycyclopentane-1,2-dicarboxylate (3.84 g, 13.1 mmol) in methanol anhydrous tetrahydrofuran (40 mL). Lithium aluminum hydride (2.00 g, 51 mmol) was partially added to the ice bath. The mixture was transferred to rt and stirred overnight. The mixture was quenched by dropping water (100 mL). The resulting mixture was adjusted to pH about 3 with hydrochloric acid (4N) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 1/2) to give the title compound as a pale yellow oil (1.60 g, 52%).

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.38-7.27 (m, 5H), 4.47 (s, 2H), 4.03-3.97 (m, 1H), 3.74-3. 66 (m, 2H), 3.47 (t, J = 9.7Hz, 1H), 3.34 (t, J = 9.9Hz, 1H), 2.23-2.05 (m, 2H), 2.05-1.96 (m, 1H), 1.96-1.84 (m, 1H), 1.53-1.38 (m, 2H).

Step 5) [4-Benzyloxy-2- (hydroxymethyl) cyclopentyl] in 5-benzyloxy-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] furan anhydrous methanol (40 mL) To a solution of methanol (1.54 g, 6.52 mmol), n-butyllithium (2.9 mL, 7.3 mmol, 2.5 mol / L) was slowly added dropwise at −20 ° C. under _N2 . The mixture was stirred for 30 minutes and a solution of p-toluenesulfochloride (1.38 g, 7.17 mmol) in anhydrous tetrahydrofuran (10 mL) was added. The mixture was transferred to rt and stirred for 1 hour. The mixture was cooled to −20 ° C. and n-butyllithium (2.9 mL, 7.3 mmol, 2.5 mol / L) was slowly added dropwise. The resulting mixture was stirred for 10 minutes, heated to 70 ° C. and stirred overnight. The mixture was quenched by dropping water (50 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 5/1) to give the title compound as a colorless oil (1.22 g, 85.8%).

MS (ESI, pose.ion) m / z: 219.1 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.41-7.28 (m, 5H), 4.55 (dd, J = 13.2, 6.6 Hz, 1H), 4.50 (s, 2H), 3.90 (dt, J = 11.3, 6.9Hz, 2H), 3.38 (dd, J = 10.9, 7.1Hz, 1H), 3.30 (dd, J = 10.9,) 7.1Hz, 1H), 2.50-2.36 (m, 1H), 2.29 (dt, J = 12.6, 6.5Hz, 1H), 2.04-1.88 (m, 2H) ), 1.55 (td, J = 12.7, 7.7 Hz, 1H), 1.44 (td, J = 12.3, 5.5 Hz, 1H).

Step 6) 3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] furan-5-ol 5-benzyloxy-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [C] Franc (1.22 g, 5.59 mmol) was dissolved in anhydrous methanol (10 mL), and glacial acetic acid (6 mL) and Pd / C (0.15 g, 10%) were added. The mixture was stirred at rt for 3 hours under hydrogen pressure of 5 Mpa. The reaction was stopped and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL). The mixture was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (EtOAc) to give the title compound as a colorless oil (0.60 g, 83.8%).

Step 7) 2- (3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] furan-5-oxy) -2- (2-methoxyphenyl) acetic acid 3,3a, 4,5 6,6a-Hexahydro-1H-cyclopenteno [c] furan-5-ol (0.60 g, 4.68 mmol) was dissolved in tetrahydrofuran (25 mL). The mixture was cooled to 0 ° C. under N ₂ and sodium hydride (0.75 g, 19 mmol, 60%) was added. The mixture was stirred for 10 minutes and then at rt for 30 minutes, then 2-bromo-2- (2-fluorophenyl) acetic acid (1.15 g, 4.69 mmol) was added. The resulting mixture was stirred at rt for 4.5 hours. The mixture was poured into ice water (50 g) to quench the reaction, then ethyl acetate (40 mL) was added. The mixture was stirred for 10 minutes. After partitioning the mixture, the aqueous phase was adjusted to pH about 2 with dilute hydrochloric acid (4N) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (1.29 g, 94.3%).

MS (ESI, neg.ion) m / z: 291.3 [MH] ^- .

Step 8) 2- (3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] furan-5-oxy) -2- (2-methoxyphenyl) ethanol 2- (3,3a, 4) , 5, 6, 6a-Hexahydro-1H-cyclopenteno [c] furan-5-oxy) -2- (2-methoxyphenyl) acetic acid (1.29 g, 4.41 mmol) was dissolved in tetrahydrofuran (30 mL). The mixture was cooled to −5 ° C. under N ₂ and lithium aluminum hydride (0.34 g, 9.0 mmol) was added in portions. The mixture was stirred overnight. The mixture was quenched by dropping water (30 mL). The resulting mixture was adjusted to pH about 2 with hydrochloric acid (4N) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 1/1) to give the title compound as a pale yellow oil (0.566 g, 46.1%).

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.38 (t, J = 6.2 Hz, 1H), 7.31-7.26 (m, 1H), 7.00 (t, J = 7.5 Hz, 1H) ), 6.88 (d, J = 8.2Hz, 1H), 4.94 (dd, J = 8.2, 3.2Hz, 1H), 4.43 (dd, J = 32.3, 6. 7Hz, 1H), 3.95-3.85 (m, 2H), 3.84 (s, 3H), 3.71-3.64 (m, 1H), 3.54 (dt, J = 11. 4, 7.7Hz, 1H), 3.42-3.33 (m, 1H), 3.28-3.22 (m, 1H), 2.50-2.26 (m, 1H), 2. 25-2.10 (m, 1H), 1.94-1.89 (m, 1H), 1.87-1.79 (m, 1H), 1.51-1.41 (m, 2H).

Step 9) 2- [1- [2- (3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] furan-5-oxy) -2- (2-methoxyphenyl) ethyl]- 5-Methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl (diphenyl) silyl 2- (3) , 3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] furan-5-oxy) -2- (2-methoxyphenyl) ethanol (0.212 g, 0.762 mmol), diisopropyl azodicarboxylate (. 0.2 mL, 1.0 mmol) and 2-methyl-2- (5-methyl-6-oxazol-2-yl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) -T-Butyl (diphenyl) silyl (0.350 g, 0.61 mmol) of propionate was dissolved in tetrahydrofuran (10.0 mL). Triphenylphosphine (0.245 mg, 0.915 mmol) was added to the mixture in portions under _N2 . The mixture was stirred at rt for 18 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 2/1) to give the title compound as a grayish white solid (0. 390 g, 76.6%).

Step 10) 2- [1- [2- (3,3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] furan-5-oxy) -2- (2-methoxyphenyl) ethyl]- 5-Methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid 2- [1- [2- (3,3) 3a, 4,5,6,6a-hexahydro-1H-cyclopenteno [c] furan-5-oxy) -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2, 4-Dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl (diphenyl) silyl (0.190 g, 0.228 mmol) is dissolved in tetrahydrofuran (2.0 mL). did. A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mol / L, 0.35 mL, 0.35 mmol) was added to the mixture. The mixture was stirred at rt for 2 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a white solid (0.071 g, 52%).

MS (ESI, pose.ion) m / z: 596.3 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.72 (s, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.34-7.29 (m, 1H), 7.24 ( s, 1H), 7.05 (t, J = 7.4Hz, 1H), 6.88 (d, J = 8.2Hz, 1H), 5.26 (dd, J = 13.1, 6.0Hz) , 1H), 4.34-4.26 (m, 1H), 4.24-4.04 (m, 2H), 3.88 (s, 3H), 3.85-3.78 (m, 2H) ) 3.31-3.24 (m, 1H) 3.20 (dd, J = 10.9, 7.1Hz, 1H) 2.86 (s, 3H) 2.28-2.19 (M, 2H), 1.88 (s, 3H), 1.84 (s, 3H), 1.81-1.75 (m, 1H), 1.61 (dd, J = 13.1, 6) .2Hz, 1H), 1.43-1.34 (m, 1H), 1.19-1.06 (m, 1H).

工程１）（３ａＲ，６ａＳ）－５－［２－ヒドロキシ－１－（２－メトキシフェニル）エトキシ］－２－メチル－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オール
（３ａＲ，６ａＳ）－５－［２－ヒドロキシ－１－（２－メトキシフェニル）エトキシ］－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オン（３００ｍｇ、１．０ｍｍｏｌ）を無水テトラヒドロフラン（５０ｍＬ）にＮ_２下で溶解した。混合物を－１０℃まで冷却し、エチルエーテル中のメチルマグネシウムブロミドの溶液（３ｍＬ、９ｍｍｏｌ、３ｍｏｌ／Ｌ）を滴下した。滴下の後、混合物を０℃で１時間撹拌した。反応を飽和含水塩化アンモニウム（５ｍＬ）でクエンチした。混合物を濃縮して溶媒を除去した。残分に、水（３０ｍＬ）及びＥｔＯＡｃ（４０ｍＬ）を添加し、混合物を分配した。有機層を無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮した。残分をシリカゲルカラムクロマトグラフィーＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ＝１／１）で精製して、標題化合物を白色の固体として得た（１８０ｍｇ、５７％）。 Example 14: 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-5-methyl-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- Propanic acid

Step 1) (3aR, 6aS) -5- [2-Hydroxy-1- (2-methoxyphenyl) ethoxy] -2-methyl-3,3a, 4,5,6,6a-hexahydro-1H-pentalene-2 -All (3aR, 6aS) -5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-hexahydro-1H-pentalene-2-one (300 mg, 1.0 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) under _N2 . The mixture was cooled to −10 ° C. and a solution of methyl magnesium bromide in ethyl ether (3 mL, 9 mmol, 3 mol / L) was added dropwise. After the dropping, the mixture was stirred at 0 ° C. for 1 hour. The reaction was quenched with saturated hydrous ammonium chloride (5 mL). The mixture was concentrated to remove the solvent. Water (30 mL) and EtOAc (40 mL) were added to the residue and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography PE / EtOAc (V / V = 1/1) to give the title compound as a white solid (180 mg, 57%).

Step 2) 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-5-methyl-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl) oxy) ) -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- (3aR, 6aS) -5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -2-methyl-3,3a, 4, in tetrahydrofuran (10 mL) t-butyl (diphenyl) silyl anhydride 5,6,6a-Hexahydro-1H-pentalene-2-ol (180 mg, 0.59 mmol), 2-methyl-2- (5-methyl-6-oxazole-2-yl-2,4-dioxo-1H-) Diisopropyl azodicarboxylate in a solution of t-butyl (diphenyl) silyl (280 mg, 0.49 mmol) of thieno [2,3-d] pyrimido-3-yl) -propionate and triphenylphosphine (310 mg, 1.18 mmol). (0.24 mL, 1.2 mmol) was slowly added dropwise at 0 ° C. under _N2 . After the dropping, the mixture was stirred for 14 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 10/1) to give the title compound as a pale yellow solid (148 mg). , 29%).

Step 3) 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-5-methyl-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-5-methyl-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-" in tetrahydrofuran (10 mL) of propanoic acid 2-yl) oxy) -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.5 mL, 1 mol / L) was added to a solution of t-butyl (diphenyl) silyl (145 mg, 0.17 mmol) of -2-methyl-propionate. The mixture was stirred for 3 hours. The mixture was concentrated. Water (30 mL) and ethyl acetate (30 mL) were added to the residue. The resulting mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound (30 mg, 27.5%).

MS (ESI, pose.ion) m / z: 646.2 [M + Na] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.71 (s, 1H), 7.51 (dd, J = 7.5, 1.3 Hz, 1H), 7.31-7.27 (m, 1H), 7.24 (s, 1H), 7.01 (t, J = 7.4Hz, 1H), 6.87 (d, J = 8.2Hz, 1H), 5.29 (dd, J = 8.8) 4.0Hz, 1H), 4.32-4.24 (m, 1H), 4.01-3.96 (m, 1H), 3.89 (s, 3H), 3.81-3.71 (M, 1H), 2.83 (s, 3H), 2.28-2.37 (m, 2H), 1.99-1.89 (m, 2H), 1.86 (s, 3H), 1.83 (s, 3H), 1.80-1.75 (m, 2H), 1.73-1.68 (m, 1H), 1.66-1.63 (m, 2H), 1. 58-1.50 (m, 1H), 1.24 (s, 3H).

工程１）２－［１－［２－［［（３ａＲ，６ａＳ）－５－シアノ－１，２，３，３ａ，４，５，６，６ａ－オクタヒドロペンタレン－２－イル）オキシ］－２－（２－メトキシフェニル）エチル］－５－メチル－６－オキサゾール－２－イル－２，４－ジオキソ－チエノ［２，３－ｄ］ピリミド－３－イル］－２－メチル－プロピオン酸ｔ－ブチル
２－［１－［２－［［（３ａＲ，６ａＳ）－５－オキサ－２，３，３ａ，４，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレニル－２－イル）オキシ］エチル］－５－メチル－６－オキサゾール－２－イル－２，４－ジオキソ－チエノ［２，３－ｄ］ピリミド－３－イル］－２－メチル－プロピオン酸ｔ－ブチル（例８の工程１に従って調製した）（０．４７ｇ、０．７１ｍｍｏｌ）、ｐ－トルエンスルホニルメチルイソシアニド（０．３２ｇ、１．８ｍｍｏｌ）及びエタノール（０．２０ｍＬ、３．４ｍｍｏｌ）をエチレングリコールジメチルエーテル（１０ｍＬ）に溶解した。次いで、カリウムｔ－ブトキシド（０．２５ｇ、２．２ｍｍｏｌ）を一部ずつ添加した。混合物をｒｔで４時間撹拌し、反応混合物を真空濃縮して溶媒を除去し、残分をシリカゲルカラムクロマトグラフィー（ＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ）＝３／１）で精製して、標題化合物を無色の油として得た（０．１５ｇ、３１．２％）。 Example 15: 2- [1- [2-[(5-cyano-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl) oxy] -2- (2-) Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid

Step 1) 2- [1- [2-[[(3aR, 6aS) -5-cyano-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl) oxy] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propion Acid t-butyl 2- [1- [2-[[(3aR, 6aS) -5-oxa-2,3,3a,4,6,6a-hexahydro-1H-pentarenyl-2-yl) oxy] ethyl] -5-Methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionate t-butyl (according to step 1 of Example 8) (Prepared) (0.47 g, 0.71 mmol), p-toluenesulfonylmethylisocyanide (0.32 g, 1.8 mmol) and ethanol (0.20 mL, 3.4 mmol) were dissolved in ethylene glycol dimethyl ether (10 mL). Then, potassium t-butoxide (0.25 g, 2.2 mmol) was added in portions. The mixture is stirred at rt for 4 hours, the reaction mixture is vacuum concentrated to remove the solvent and the residue is purified by silica gel column chromatography (PE / EtOAc (V / V) = 3/1) to give the title compound. Obtained as a colorless oil (0.15 g, 31.2%).

Step 2) 2- [1- [2-[[(3aR, 6aS) -5-cyano-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl) oxy] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propane Acid 2- [1- [2-[[(3aR, 6aS) -5-cyano-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl) oxy] -2 -(2-Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t -Butyl (0.25 g, 0.37 mmol) was dissolved in EtOAc (5 mL) with rt and a solution of hydrogen chloride in ethyl acetate (10 mL) was added. The mixture was stirred for 6 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 1/1) to give the title compound as a white solid (0. 21 g, 92.0%).

MS (ESI, pose.ion) m / z: 619.1 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.73 (s, 1H), 7.49 (d, J = 6.6 Hz, 1H), 7.34-7.29 (m, 1H), 7.24 ( s, 1H), 7.04 (t, J = 7.7Hz, 1H), 6.87 (d, J = 8.0Hz, 1H), 5.33-5.26 (m, 1H), 4. 13-4.02 (m, 2H), 3.85 (s, 3H), 3.75-3.70 (m, 1H), 2.87 (s, 3H), 2.85-2.76 ( m, 1H), 2.52-2.50 (m, 2H), 2.00-1.92 (m, 5H), 1.88 (s, 3H), 1.86 (s, 3H), 1 .77-1.70 (m, 3H).

工程１）［２－［［（３ａＲ，６ａＳ）－５－ベンジルオキシ－１，２，３，３ａ，４，５，６，６ａ－オクタヒドロペンタレン－２－イル］オキシ］－２－（２－メトキシフェニル）エトキシ］－ｔ－ブチルジメチルシラン
［２－［［（３ａＲ，６ａＳ）－５－ベンジルオキシ－１，２，３，３ａ，４，５，６，６ａ－オクタヒドロペンタレン－２－イル）オキシ］－２－（２－メトキシフェニル）エタノール（１．００ｇ、２．６１ｍｍｏｌ）をＤＣＭ（２０ｍＬ）に溶解し、次いで、イミダゾール（３６０ｍｇ、５．２３ｍｍｏｌ）を添加した。溶液を０℃まで冷却した。次いで、ｔ－ブチルジメチルシリルクロリド（５９１ｍｇ、３．９２ｍｍｏｌ）を滴下した。混合物を０℃で３５分間撹拌した。混合物に水（１０ｍＬ）を添加し、混合物を１０分間撹拌した。混合物を分配した後。水相をＤＣＭ（２０ｍＬ×２）で抽出した。併せた有機相を飽和塩水で洗浄し、無水硫酸ナトリウム上で乾燥し、濾過した。濾液を真空濃縮した。残分をシリカゲルクロマグラフィー（ＥｔＯＡｃ／ＰＥ（Ｖ／Ｖ）＝１／１２）で精製して、標題化合物を淡黄色の固体として得た（１．２３ｇ、９４．７％）。 Example 16: 2- [1- [2-[[(3aR, 6aS) -5-methoxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methylpropanoic acid

Step 1) [2-[[(3aR, 6aS) -5-benzyloxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2-( 2-Methoxyphenyl) ethoxy] -t-butyldimethylsilane [2-[[(3aR, 6aS) -5-benzyloxy-1,2,3,3a,4,5,6,6a-octahydropentalene- 2-Il) oxy] -2- (2-methoxyphenyl) ethanol (1.00 g, 2.61 mmol) was dissolved in DCM (20 mL), followed by the addition of imidazole (360 mg, 5.23 mmol). The solution was cooled to 0 ° C. Then, t-butyldimethylsilyl chloride (591 mg, 3.92 mmol) was added dropwise. The mixture was stirred at 0 ° C. for 35 minutes. Water (10 mL) was added to the mixture and the mixture was stirred for 10 minutes. After dispensing the mixture. The aqueous phase was extracted with DCM (20 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromography (EtOAc / PE (V / V) = 1/12) to give the title compound as a pale yellow solid (1.23 g, 94.7%).

MS (ESI, pose.ion) m / z: 519.2 [M + Na] ⁺ .

Step 2) (3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -1,2,3,3a, 4,5,6 6a-Octahydropentalene-2-ol [2-[[(3aR, 6aS) -5-benzyloxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl ] Oxy] -2- (2-methoxyphenyl) ethoxy] -t-butyldimethylsilane (1.23 g, 2.48 mmol) dissolved in methanol (20.0 mL), followed by palladium carbon (123 mg, 0.12 mmol). 10%) was added. The mixture was stirred at rt under H2 for ₃ hours. The mixture was filtered and the filter cake was washed with methanol (20.0 mL). The filtrate was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (EtOAc / PE (V / V) = 1/12) to give the title compound as a pale yellow oil (0. 88 g, 87.4%).

MS (ESI, pose.ion) m / z: 429.3 [M + Na] ⁺ .

Step 3) 2-[[(3aR, 6aS) -5-methoxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-) Methoxyphenyl) ethoxy] -t-butyldimethylsilane (3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -1,2,3 3a, 4,5,6,6a-octahydropentalene-2-ol (200 mg, 0.49 mmol) was dissolved in tetrahydrofuran (5.0 mL). The mixture was cooled to 0 ° C. under _N2 and sodium hydride (24 mg, 0.60 mmol, 60%) was added in portions. The mixture was stirred for 0.5 hours. Iodomethane (77.2 mg, 0.54 mmol) was slowly added dropwise to the mixture and the mixture was stirred at rt for 24 hours. Water (10 mL) was then added to the mixture and the mixture was stirred for 10 minutes. After dispensing the mixture. The aqueous phase was extracted with DCM (20 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 15/1) to give the title compound as a pale yellow solid (178 mg, 86.0%).

MS (ESI, pose.ion) m / z: 443.4 [M + Na] ⁺ .

Step 4) 2-[[(3aR, 6aS) -5-methoxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-) Methoxyphenyl) Ethanol 2-[[(3aR, 6aS) -5-methoxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2) -Methoxyphenyl) ethoxy] -t-butyldimethylsilane (178 mg, 0.42 mmol) was dissolved in tetrahydrofuran (2.0 mL), and then tetrabutylammonium fluoride (1.3 mL, 1.30 mmol) was added. The mixture was stirred at rt for 3 hours. The mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 4/1) to give the title compound as a grayish white solid (125 mg, 96.4%).

MS (ESI, pose.ion) m / z: 329.2 [M + Na] ⁺ .

Step 5) 2- [1- [2-[[(3aR, 6aS) -5-methoxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-Methoxyphenyl) ethyl) -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propion Acid t-butyl (diphenyl) silyl 2-[[(3aR, 6aS) -5-methoxy-1,2,3,3a,4,5,6,6a-octahydropentalene-2-yl] oxy]- 2- (2-Methoxyphenyl) ethanol (337 mg, 1.10 mmol), triphenylphosphine (555 mg, 2.09 mmol) and 2-methyl-2- (5-methyl-6-oxazole-2-yl-2,4) -Dioxo-1H-thieno [2,3-d] pyrimido-3-yl) t-butyl (diphenyl) silyl (600 mg, 1.05 mmol) propionate was added to tetrahydrofuran (20.0 mL). The mixture was stirred under N ₂ for 5 minutes, and diisopropyl azodicarboxylate (432 mg, 2.09 mmol) was added dropwise. The mixture was stirred at rt for 3.5 hours and concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 8/1) to give the title compound as a pale yellow oil (450 mg, 49.9%).

Step 6) 2- [1- [2-[[(3aR, 6aS) -5-methoxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methylpropanoic acid 2- [1- [2-[[(3aR, 6aS) -5-methoxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-Methoxyphenyl) ethyl) -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t- Butyl (diphenyl) silyl (450 mg, 0.52 mmol) was dissolved in tetrahydrofuran (5.0 mL). A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mol / L, 3.2 mL, 3.20 mmol) was added to the mixture. The mixture was stirred at rt for 2 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a grayish white solid (30 mg, 9.2%).

MS (ESI, pose.ion) m / z: 624.1 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.66 (s, 1H), 7.59-7.52 (m, 1H), 7.29-7.25 (m, 1H), 7.21 (s, 1H), 7.00 (t, J = 7.4Hz, 1H), 6.86 (d, J = 8.2Hz, 1H), 5.17-5.15 (m, 1H), 4.63- 4.59 (m, 1H), 4.50-4.47 (m, 1H), 3.85 (s, 3H), 3.83-3.76 (m, 2H), 3.31 (s, 3H), 2.84 (s, 3H), 2.38-2.26 (m, 2H), 2.11-2.07 (m, 1H), 2.01-1.95 (m, 2H) 1.90-1.86 (m, 5H), 1.76 (s, 3H), 1.73-1.68 (m, 2H).

工程１）（３’ａＳ，６’ａＲ）－２’－フルオロ－５，５－ジメチル－スピロ［１，３－ジオキサン－２，５’－２，３，３ａ，４，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン］
ＤＣＭ（１０ｍＬ）中の（３ａ’Ｒ，６ａ’Ｓ）－５，５－ジメチルスピロ［１，３－ジオキサン－２，５’－２，３，３ａ，４，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン］－５’－オール（２．０ｇ、８．８ｍｍｏｌ）の溶液に、三フッ化ジエチルアミノ硫黄（２．３ｍＬ、１８ｍｍｏｌ）をゆっくりと０℃で滴下した。混合物をｒｔに移し、１７時間撹拌した。混合物を氷水（１００ｍＬ）に注ぎ入れ、反応をクエンチし、次いで、ＤＣＭ（５０ｍＬ）で抽出し、次いで、真空濃縮して、標題化合物を黒色の油として得た（２．０ｇ、９９％）。 Example 17: 2- [1- [2-[[(3aR, 6aS) -5-fluoro-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-Methoxyphenyl) ethyl) -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propane acid

Step 1) (3'aS, 6'aR) -2'-fluoro-5,5-dimethyl-spiro [1,3-dioxane-2,5'-2,3,3a, 4,6,6a-hexahydro -1H-Pentalene]
(3a'R, 6a'S) -5,5-dimethylspiro [1,3-dioxane-2,5'-2,3,3a, 4,6,6a-hexahydro-1H-" in DCM (10 mL) Pentalene] In a solution of -5'-ol (2.0 g, 8.8 mmol), diethylaminosulfur trifluoride (2.3 mL, 18 mmol) was slowly added dropwise at 0 ° C. The mixture was transferred to rt and stirred for 17 hours. The mixture was poured into ice water (100 mL), the reaction was quenched, then extracted with DCM (50 mL) and then vacuum concentrated to give the title compound as a black oil (2.0 g, 99%).

Step 2) (3'aS, 6'aR)-(3'aS, 6'aR) in (3aS, 6aR) -5-fluoro-3,3a, 4,5,6,6a-hexahydro-1H-pentalene-2-one hydrochloride (20 mL) 2'-Fluoro-5,5-dimethyl-spiro [1,3-dioxane-2,5'-2,3,3a, 4,6,6a-hexahydro-1H-pentalene] (2.0 g, 8.8 mmol) ), Concentrated hydrochloric acid (2 mL, 36%) was added at rt. The mixture was stirred for 2 hours. The mixture was concentrated. Water (100 mL) and ethyl acetate (100 mL) were added to the residue. The resulting mixture was dispensed. The organic layer was adjusted to pH about neutral, dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a brown oil (0.77 g, 62%).

Step 3) (3aR, 6aS) -5-fluoro-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-ol (3aS, 6aR) -5 in methanol (5 mL) -Sodium borohydride (0.31 g, 8.2 mmol) in a solution of fluoro-3,3a, 4,5,6,6a-hexahydro-1H-pentalene-2-one (0.77 g, 5.4 mmol). Was added at 0 ° C. The mixture was stirred for 30 minutes. The reaction was quenched with water (2 mL). The mixture was concentrated. Water (40 mL) and EtOAc (40 mL) were added to the residue and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (V / V = 10/1)) to give the title compound as a colorless oil (530 mg, 68%).

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ5.28-5.15 (m, 1H) 4.37-4-32 (m, 1H) 2.76-2.62 (m, 2H) 2. 30-2.16 (m, 2H), 2.12-2.03 (m, 2H), 1.79-1.73 (m, 1H), 1.69-1.62 (m, 1H).

Step 4) 2-[[(3aR, 6aS) -5-fluoro-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl) oxy) -2- (2-) (Methoxyphenyl) acetic acid (3aR, 6aS) -5-fluoro-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-ol (300 mg, 2. Sodium hydride (340 mg, 60%) was added to the solution (1 mmol) at 0 ° C. The mixture was stirred for 1 hour and a solution of 2-bromo-2- (2-methoxyphenyl) acetic acid (510 mg, 2.1 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise. After the dropping, the mixture was transferred to rt and stirred for 16 hours. The mixture was cooled to 0 ° C. and quenched with water (5 mL). The mixture was concentrated and water (100 mL) and ethyl acetate (100 mL) were added to the residue and the resulting mixture was dispensed. The combined aqueous layer was adjusted to pH about 2 with hydrochloric acid (4N) and then extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (350 mg, 54.56%).

LC-MS (ES / API, pose.ion) m / z: 331.0 [M + Na] ⁺ .

Step 5) 2-[[(3aR, 6aS) -5-fluoro-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-) 2-[[(3aR, 6aS) -5-fluoro-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl) in anhydrous tetrahydrofuran (10 mL) of methoxyphenyl) ethanol Lithium aluminum hydride (26 mg, 0.68 mmol) was added to a solution of oxy) -2- (2-methoxyphenyl) acetic acid (350 mg, 1.14 mmol) at 0 ° C. After the addition, the mixture was transferred to rt and stirred for 2 hours. The mixture was cooled to 0 ° C. and quenched with water (1 mL). The mixture was concentrated to remove most of the solvent. Hydrochloric acid (100 mL, 4N) was added to the residue, the mixture was stirred for 5 minutes and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (V / V = 6/1)) to give the title compound as a colorless oil (210 mg, 62.83%).

MS (ES / API, pose.ion) m / z: 317.1 [M + Na] ^{+
1 1} H NMR (400 MHz, CDCl ₃ ) δ7.35 (dd, J = 7.5, 1.4 Hz, 1H), 7.26 (dd, J = 15.7, 1.7 Hz, 1H), 6.97 (T, J = 7.4Hz, 1H), 6.87 (d, J = 8.2Hz, 1H), 5.20 (d, J = 53.0Hz, 1H), 4.94 (dd, J = 7.9, 3.3Hz, 1H), 3.95-3.85 (m, 1H), 3.82 (s, 3H), 3.66-3.53 (m, 1H), 3.52- 3.47 (m, 1H), 2.68-2.47 (m, 2H), 2.25-2.15 (m, 2H), 2.15-2.06 (m, 2H), 2. 04-1.95 (m, 1H), 1.77-1.69 (m, 1H), 1.52-1.40 (m, 2H).

Step 6) 2- [1- [2-[[(3aR, 6aS) -5-fluoro-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-Methoxyphenyl) ethyl) -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propion 2-[[(3aR, 6aS) -5-fluoro-1,2,3,3a, 4,5,6,6a-octahydropentalene-in t-butyl (diphenyl) silyl anhydrous tetrahydrofuran (10 mL)) 2-Il] Oxy] -2- (2-Methoxyphenyl) ethanol (130 mg, 0.44 mmol), 2-methyl-2- (5-methyl-6-oxazole-2-yl-2,4-dioxo-1H) -Azodicarboxylic acid in a solution of thieno [2,3-d] pyrimido-3-yl) -propionic acid t-butyl (diphenyl) silyl (250 mg, 0.43 mmol) and triphenylphosphine (230 mg, 0.88 mmol). Diisopropyl (0.18 mL, 0.91 mmol) was slowly added dropwise at 0 ° C. under _N2 . After the dropping, the mixture was stirred at rt for 12 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 5/1) to give the title compound as a pale yellow solid (235 mg). , 62.6%).

Step 7) 2- [1- [2-[[(3aR, 6aS) -5-fluoro-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-Methoxyphenyl) ethyl) -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propane 2- [1- [2-[[(3aR, 6aS) -5-fluoro-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-] in tetrahydrofuran (10 mL)) Il] Oxy] -2- (2-methoxyphenyl) ethyl) -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2 A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.3 mL, 1 mol / L) was added at rt to a solution of t-butyl (diphenyl) silyl (235 mg, 0.28 mmol) of methyl-propionate. The mixture was stirred for 1.5 hours. The mixture was concentrated. Water (30 mL) and ethyl acetate (30 mL) were added to the residue. The resulting mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound as a white solid (109 mg, 33.0%).

MS (ES / API, pose.ion) m / z: 612.2 [M + H] ^{+
1 1} H NMR (400 MHz, CDCl ₃ ) δ7.70 (s, 1H), 7.48 (dd, J = 7.5, 1.3 Hz, 1H), 7.30-7.27 (m, 1H), 7.22 (s, 1H), 7.02 (t, J = 7.4Hz, 1H), 6.85 (d, J = 8.2Hz, 1H), 5.35-5.29 (m, 1H) ), 4.90 (d, J = 53.1Hz, 1H), 4.19-4.10 (m, 1H), 3.99-3.90 (m, 1H), 3.84 (s, 3H) ), 3.82-3.79 (m, 1H), 2.84 (s, 3H), 2.61-2.46 (m, 2H), 2.16-1.95 (m, 2H), 1.86 (s, 3H), 1.83 (s, 3H), 1.83-1.76 (m, 2H), 1.51-1.37 (m, 4H).

工程１）（３ａＲ，６ａＳ）－５－［２－ヒドロキシ－１－（２－メトキシフェニル）エトキシ］－２－（トリフルオロメチル）－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オール
テトラヒドロフラン（５０ｍＬ）中の（３ａＲ，６ａＳ）－５－［２－ヒドロキシ－１－（２－メトキシフェニル）エトキシ］－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オン（１００ｍｇ、０．３４ｍｍｏｌ）の溶液に、トリフルオロメチルトリエチルシラン（０．１５ｍＬ、１．０ｍｍｏｌ）をｒｔでＮ_２下添加した。混合物を０℃まで冷却し、ＴＨＦ中のフッ化テトラブチルアンモニウム（１．０ｍＬ、１ｍｏｌ／Ｌ）の溶液を添加した。添加の後、混合物を１２時間撹拌した。混合物を濃縮した。残分に、水（３０ｍＬ）及びＥｔＯＡｃ（３０ｍＬ）を添加し、混合物を分配した。有機層を無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮した。残分をシリカゲルカラムクロマトグラフィー（ＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ＝３／１）で精製して、標題化合物を白色の固体として得た（８８ｍｇ、７１％）。 Example 18: 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-5- (trifluoromethyl) -2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2" -Il] Oxy] -2- (2-methoxyphenyl) ethyl] -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl]- 2-Methyl-propanoic acid

Step 1) (3aR, 6aS) -5- [2-Hydroxy-1- (2-methoxyphenyl) ethoxy] -2- (trifluoromethyl) -3,3a, 4,5,6,6a-hexahydro-1H -Pentalene-2-ol (3aR, 6aS) -5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-hexahydro-in tetrahydrofuran (50 mL) To a solution of 1H-pentalene-2-one (100 mg, 0.34 mmol) was added trifluoromethyltriethylsilane (0.15 mL, 1.0 mmol) under _N2 at rt. The mixture was cooled to 0 ° C. and a solution of tetrabutylammonium fluoride (1.0 mL, 1 mol / L) in THF was added. After the addition, the mixture was stirred for 12 hours. The mixture was concentrated. Water (30 mL) and EtOAc (30 mL) were added to the residue and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (V / V = 3/1)) to give the title compound as a white solid (88 mg, 71%).

MS (ES / API, neg.ion) m / z: 405.1 [M + HCOO] ^- .

Step 2) 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-5- (trifluoromethyl) -2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2) -Il] Oxy] -2- (2-Methoxyphenyl) ethyl] -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl]- (3aR, 6aS) -5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -2- (trifluoromethyl) in t-butyl (diphenyl) silyl anhydrous tetrahydrofuran (5 mL) 2-methyl-propionate ) -3,3a, 4,5,6,6a-Hexahydro-1H-pentalen-2-ol (85 mg, 0.24 mmol), 2-methyl-2- (5-methyl-6-oxazole-2-yl-) 2,4-Dioxo-1H-thieno [2,3-d] pyrimido-3-yl) -t-butyl (diphenyl) silyl (150 mg, 0.26 mmol) -propionate and triphenylphosphine (125 mg, 0.47 mmol) Diisopropyl azodicarboxylate (0.1 mL, 0.5 mmol) was slowly added dropwise to the solution of (0.1 mL, 0.5 mmol) at 0 ° C. under _N2 . After the dropping, the mixture was stirred at rt for 5 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 4/1) to give the title compound as a pale yellow solid (140 mg). , 65%).

Step 3) 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-5- (trifluoromethyl) -2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2) -Il] Oxy] -2- (2-methoxyphenyl) ethyl] -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl]- 2-Methyl-propanoic acid 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-5-trifluoromethyl-2,3,3a, 4,6,6a-) in tetrahydrofuran (10 mL) Hexahydro-1H-pentalen-2-yl) oxy) -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] Pyrimido-3-yl] -2-methyl-propionate t-butyl (diphenyl) silyl (140 mg, 0.15 mmol) in a solution of tetrabutylammonium fluoride in tetrahydrofuran (0.5 mL, 1 mol / L) Was added by rt. The mixture was stirred for 2 hours. The mixture was concentrated. Water (30 mL) and ethyl acetate (30 mL) were added to the residue. The resulting mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound as a white solid (21 mg, 20%).

MS (ES / API, neg.ion) m / z: 676.0 [MH] ^- ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.70 (s, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.29-7.31 (m, 1H), 7.21 ( s, 1H), 7.01 (t, J = 7.4Hz, 1H), 6.89 (d, J = 8.2Hz, 1H), 5.28-5.32 (m, 1H), 4. 30-4.36 (m, 1H), 3.98-4.01 (m, 1H), 3.93 (s, 3H), 3.75-3.80 (m, 1H), 2.81 ( s, 3H), 2.46-2.38 (m, 2H), 2.17-1.90 (m, 6H), 1.81 (s, 3H), 1.79 (s, 3H), 1 .63-1.69 (m, 2H).

工程１）（３ａＲ，６ａＳ）－５－［２－［ｔ－ブチル（ジメチル）シリル］オキシ－１－（２－メトキシフェニル）エトキシ］－２－エチル－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オール
無水テトラヒドロフラン（１０ｍＬ）中の（３ａＲ，６ａＳ）－５－［２－ヒドロキシ－１－（２－メトキシフェニル）エトキシ］－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オン（２３０ｍｇ、０．５７ｍｍｏｌ）の溶液に、エチルエーテル中の臭化エチルマグネシウム（３．４ｍＬ、３．４ｍｍｏｌ、１ｍｏｌ／Ｌ）の溶液をＮ_２下、氷浴上で滴下した。滴下の後、混合物をｒｔで１時間撹拌した。反応物を水（２ｍＬ）により氷浴上でクエンチした。混合物を濃縮して溶媒の大半を除去した。残分に、水（３０ｍＬ）及びＥｔＯＡｃ（３０ｍＬ）を添加し、混合物を分配した。有機層を無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮して、標題化合物を淡黄色のシロップとして得た（２４０ｍｇ、９７．１２％）。 Example 19: 2- [1- [2-[[(3aR, 6aS) -5-ethyl-5-hydroxy-2,3,3a,4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl) -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- Propanic acid

Step 1) (3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -2-ethyl-3,3a, 4,5,6 (3aR, 6aS) -5- [2-Hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5 in 6a-hexahydro-1H-pentalene-2-ol anhydrous tetrahydrofuran (10 mL) A solution of ethylmagnesium bromide (3.4 mL, 3.4 mmol, 1 mol / L) in ethyl ether was added to a solution of 6,6a-hexahydro-1H-pentalene-2-one (230 mg, 0.57 mmol) N ₂ Below, it was dropped on an ice bath. After the dropping, the mixture was stirred at rt for 1 hour. The reaction was quenched on an ice bath with water (2 mL). The mixture was concentrated to remove most of the solvent. Water (30 mL) and EtOAc (30 mL) were added to the residue and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow syrup (240 mg, 97.12%).

MS (ES / API, pos.ion) m / z: 457.1 [M + Na] ⁺ .

Step 2) (3aR, 6aS) -2-Ethyl-5- [2-Hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-Hexahydro-1H-pentalene-2 -(3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -2-ethyl-3,3a, in all anhydrous tetrahydrofuran (20 mL), A solution of tetrabutylammonium fluoride (1 mol / L) in tetrahydrofuran (1.2 mL, 3 mol / L) in a solution of 4,5,6,6a-hexahydro-1H-pentalene-2-ol (240 mg, 0.55 mmol). L) was added in rt. After the addition, the mixture was stirred for 1 hour. The mixture was concentrated to remove most of the solvent. Water (50 mL) and EtOAc (50 mL) were added to the residue and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (V / V = 2/1)) to give the title compound as a white solid (110 mg, 62%).

MS (ES / API, pos.ion) m / z: 343.3 [M + Na] ⁺ .

Step 3) 2- [1- [2-[[(3aR, 6aS) -5-ethyl-5-hydroxy-2,3,3a,4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- (3aR, 6aS) -2-ethyl-5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4, in t-butyl (diphenyl) silyl anhydrous tetrahydrofuran (10 mL) propionate 5,6,6a-Hexahydro-1H-pentalene-2-ol (110 mg, 0.34 mmol), 2-methyl-2- (5-methyl-6-oxazole-2-yl-2,4-dioxo-1H-) Diisopropyl azodicarboxylate in a solution of t-butyl (diphenyl) silyl (200 mg, 0.35 mmol) of thieno [2,3-d] pyrimido-3-yl) -propionate and triphenylphosphine (180 mg, 0.69 mmol). (0.15 mL, 0.76 mmol) was slowly added dropwise under _N2 . After the dropping, the mixture was stirred for 3 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 8/1) to give the title compound as a pale yellow solid (240 mg). , 80%).

Step 4) 2- [1- [2-[[(3aR, 6aS) -5-ethyl-5-hydroxy-2,3,3a,4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl) -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- 2- [1- [2-[[(3aR, 6aS) -5-ethyl-5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-" in tetrahydrofuran (20 mL) of propanoic acid 2-Il) Oxy) -2- (2-Methoxyphenyl) Ethyl] -5-Methyl-6-Oxazole-2-yl-2,4-dioxo-thieno [2,3-d] Pyrimid-3-yl] A solution of tetrabutylammonium fluoride in tetrahydrofuran (2.0 mL, 1 mol / L) was added to a solution of t-butyl (diphenyl) silyl (240 mg, 0.27 mmol) of -2-methyl-propionate at rt. The mixture was stirred for 1 hour. The mixture was concentrated in vacuo. Water (50 mL) and ethyl acetate (50 mL) were added to the mixture. The resulting mixture was dispensed. The organic layer was washed with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound as a white solid (59 mg, 27%).

MS (ES / API, neg.ion) m / z: 636.2 [MH] ^- ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.70 (s, 1H), 7.53 (d, J = 6.5 Hz, 1H), 7.30 (d, J = 7.1 Hz, 1H), 7. 22 (s, 1H), 7.02 (t, J = 7.5Hz, 1H), 6.88 (d, J = 8.2Hz, 1H), 5.27-5.30 (m, 1H), 4.30-4.34 (m, 1H), 3.91 (s, 3H), 3.90-3.83 (m, 1H), 3.78-3.68 (m, 1H), 2. 85 (s, 3H), 2.32-2.28 (m, 2H), 2.00-1.95 (m, 2H), 1.88 (s, 3H), 1.83 (s, 3H) 1.82-1.71 (m, 4H), 1.58-1.61 (m, 2H), 1.47-1.53 (m, 2H), 0.89 (t, 3H).

標題化合物を例１に記載の方法に従って２－ブロモ－２－（２－フルオロフェニル）酢酸（１６５ｍｇ、０．８４ｍｍｏｌ）から調製した。標題化合物を灰白色の固体として得た（３０ｍｇ、２３．２％）。 Example 20: 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2-Fluorophenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propane acid

The title compound was prepared from 2-bromo-2- (2-fluorophenyl) acetic acid (165 mg, 0.84 mmol) according to the method described in Example 1. The title compound was obtained as a grayish white solid (30 mg, 23.2%).

MS (ESI, pose.ion) m / z: 598.3 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.70 (s, 1H), 7.55 (t, J = 6.8 Hz, 1H), 7.34-7.29 (m, 6.8 Hz, 1H), 7.24-7.18 (m, 2H), 7.07 (t, J = 9.2Hz, 1H), 5.28 (t, J = 6.4Hz, 1H), 4.16-4.11 (M, 3H), 3.83-3.74 (m, 1H), 2.84 (s, 3H), 2.28-2.23 (m, 2H), 2.07-1.91 (m) , 4H), 1.87 (s, 3H), 1.83 (s, 3H), 1.68-1.61 (m, 2H), 1.60-1.53 (m, 2H).

工程１）（３ａＲ，６ａＳ）－５，５－ジフルオロ－５’，５’－ジメチル－スピロ［１，３，３ａ，４，６，６ａ－ヘキサヒドロペンタレニル－２，２’－１，３－ジオキサン］
ＤＣＭ（１０ｍＬ）中の（３ａＲ，６ａＳ）－５’，５’－ジメチルスピロ［１，３，３ａ，４，６，６ａ－ヘキサヒドロペンタレニル－５，２’－１，３－ジオキサン］－２－オン（２．０ｇ、８．９ｍｍｏｌ）の溶液に、三フッ化ジエチルアミノ硫黄（４．０ｍＬ、３１ｍｍｏｌ）をゆっくりと０℃で滴下した。混合物をｒｔに移し、１６時間撹拌した。混合物を氷水（１００ｍＬ）に注ぎ入れ反応をクエンチし、次いで、ＤＣＭ（５０ｍＬ）で抽出し、次いで、真空濃縮して、標題化合物を黒色の油として得た（２．１ｇ、９６％）。 Example 21: 2- [1- [2-[[(3aR, 6aS) -5,5-difluoro-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl] oxy]- 2- (2-Methoxyphenyl) ethyl) -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid

Step 1) (3aR, 6aS) -5,5-difluoro-5', 5'-dimethyl-spiro [1,3,3a, 4,6,6a-hexahydropentarenyl-2,2'-1, 3-Dioxane]
(3aR, 6aS) -5', 5'-dimethylspiro [1,3,3a, 4,6,6a-hexahydropentarenyl-5,2'-1,3-dioxane] in DCM (10 mL) Diethylaminosulfur trifluoride (4.0 mL, 31 mmol) was slowly added dropwise at 0 ° C. to a solution of -2-one (2.0 g, 8.9 mmol). The mixture was transferred to rt and stirred for 16 hours. The mixture was poured into ice water (100 mL) to quench the reaction, then extracted with DCM (50 mL) and then vacuum concentrated to give the title compound as a black oil (2.1 g, 96%).

Step 2) (3aR, 6aS) -5,5-difluoro-1,3,3a, 4,6,6a-hexahydropentalene-2-one in tetrahydrofuran (20 mL) (3aR, 6aS) -5,5 -Difluoro-5', 5'-dimethyl-spiro [1,3,3a, 4,6,6a-hexahydropentarenyl-2,2'-1,3-dioxane] (2.1 g, 8.5 mmol) ), Concentrated hydrochloric acid (2 mL, 36%) was added in THF. The mixture was stirred at rt for 1 hour. The mixture was concentrated. Water (100 mL) and ethyl acetate (100 mL) were added to the residue. The resulting mixture was dispensed. The organic layer was adjusted to pH about neutral, dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a brown oil (0.96 g, 70%).

Step 3) (3aR, 6aS) -5,5-difluoro-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-ol (3aR, 6aS) -5 in methanol (10 mL) Sodium borohydride (0.35 g, 9.3 mmol) in a solution of 5-difluoro-1,3,3a, 4,6,6a-hexahydropentalene-2-one (0.96 g, 6.0 mmol). Was added at 0 ° C. The mixture was stirred for 15 minutes. The reaction was quenched with water (2 mL). The mixture was concentrated to remove the solvent. Water (40 mL) and EtOAc (40 mL) were added to the residue and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (V / V = 6/1)) to give the title compound as a colorless oil (360 mg, 37%).

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ4.34-4.26 (m, 1H) 2.68-2.55 (m, 2H) 2.22-2.34 (m, 2H) 2. 15-1.99 (m, 4H), 1.59-1.51 (m, 2H).

Step 4) 2-[[(3aR, 6aS) -5,5-difluoro-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] -2- (2-methoxy Phenyl) Acetic acid (3aR, 6aS) -5,5-difluoro-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-ol (350 mg, 2.16 mmol) in anhydrous tetrahydrofuran (10 mL). Sodium hydride (340 mg, 8.5 mmol, 60%) was added to the solution of the above at 0 ° C. The mixture was stirred for 1 hour and a solution of 2-bromo-2- (2-methoxyphenyl) acetic acid (530 mg, 2.16 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise. After the dropping, the mixture was transferred to rt and stirred for 17 hours. The mixture was cooled to 0 ° C. and quenched with water (5 mL). The mixture was concentrated to remove most of the solvent, water (30 mL) and ethyl acetate (30 mL) were added to the residue and the resulting mixture was dispensed. The combined aqueous layer was adjusted to pH about 2 with hydrochloric acid (4N) and then extracted with ethyl acetate (40 mL). The organic layer was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (610 mg, 86.6%).

Step 5) 2-[[(3aR, 6aS) -5,5-difluoro-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] -2- (2-methoxy Phenyl) Ethanol 2-[[(3aR, 6aS) -5,5-difluoro-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] in anhydrous tetrahydrofuran (20 mL)] Lithium aluminum hydride (280 mg, 7.38 mmol) was added to a solution of -2- (2-methoxyphenyl) acetic acid (610 mg, 1.87 mmol) at 0 ° C. After the addition, the mixture was transferred to rt and stirred for 2 hours. The mixture was quenched with water (5 mL). The mixture was concentrated in vacuo to remove the solvent. Hydrochloric acid (50 mL, 4N) was added to the residue, the mixture was stirred for 5 minutes and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (V / V = 6/1)) to give the title compound as a colorless oil (320 mg, 55%).

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.36 (d, J = 7.5 Hz, 1H), 7.24-2.29 (m, 1H), 6.98 (t, J = 7.3 Hz, 1H) ), 6.87 (d, J = 8.2Hz, 1H), 4.94-4.97 (m, 1H), 3.83-3.88 (m, 1H), 3.82 (s, 3H). ), 3.70-3.62 (m, 1H), 3.51-3.57 (m, 1H), 2.59-2.44 (m, 2H), 2.32-2.19 (m) , 2H), 2.16-2.09 (m, 2H), 2.04-1.93 (m, 2H), 1.69-1.60 (m, 2H).

Step 6) 2- [1- [2-[[3aR, 6aS) -5,5-difluoro-2,3,3a,4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] -2 -(2-Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t -Butyl (diphenyl) Cyril 2-[[(3aR, 6aS) -5,5-difluoro-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl) in anhydrous tetrahydrofuran (10 mL) ] Oxy] -2- (2-methoxyphenyl) ethanol (320 mg, 1.0 mmol), 2-methyl-2- (5-methyl-6-oxazol-2-yl-2,4-dioxo-1H-thieno] 2,3-d] Diisopropyl azodicarboxylate (0) in a solution of t-butyl (diphenyl) silyl (580 mg, 1.0 mmol) pyrimido-3-yl) -propionate and triphenylphosphine (540 mg, 2.06 mmol). .40 mL, 2.0 mmol) was slowly added dropwise at 0 ° C. under _N2 . After the dropping, the mixture was stirred at rt for 15 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 5/1) to give the title compound as a pale yellow syrup (736 mg). , 83%).

Step 7) 2- [1- [2-[[(3aR, 6aS) -5,5-difluoro-2,3,3a,4,6,6a-hexahydro-1H-pentalene-2-yl] oxy]- 2- (2-Methoxyphenyl) ethyl) -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid 2- [1- [2-[[3aR, 6aS) -5,5-difluoro-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl] oxy in tetrahydrofuran (10 mL) ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- A solution of tetrabutylammonium fluoride (2.5 mL, 1 mol / L) in tetrahydrofuran was added to a solution of t-butyl (diphenyl) silyl (736 mg, 0.85 mmol) of propionate at rt. The mixture was stirred at rt for 1 hour. The mixture was concentrated. Water (100 mL) and EtOAc (100 mL) were added to the residue and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a white solid (118 mg, 22%).

MS (ES / API, pose.ion) m / z: 630.1 [M + H] ^{+
1 1} H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.50 (d, J = 6.4 Hz, 1H), 7.30-7.23 (m, 1H), 7.21 ( s, 1H), 7.02 (t, J = 7.4Hz, 1H), 6.84 (d, J = 8.2Hz, 1H), 5.33-5.28 (m, 1H), 4. 16-4.11 (m, 1H), 4.04-4.00 (m, 1H), 3.82 (s, 3H), 3.83-3.78 (m, 1H), 2.83 ( s, 3H), 2.49-2.41 (m, 2H), 2.23-2.03 (m, 6H), 1.87 (s, 3H), 1.83 (s, 3H), 1 .55-1.46 (m, 2H).

工程１）［２－［［（３ａＲ，６ａＳ）－５－ベンジルオキシ－１，２，３，３ａ，４，５，６，６ａ－オクタヒドロペンタレン－２－イル］オキシ］－２－（２－メトキシフェニル）エトキシ］－ｔ－ブチル－ジメチルシラン
ＤＣＭ（３０ｍＬ）中の２－［［（３ａＲ，６ａＳ）－５－ベンジルオキシ－１，２，３，３ａ，４，５，６，６ａ－オクタヒドロペンタレン－２－イル］オキシ］－２－（２－メトキシフェニル）エタノール（２．６０ｇ、６．８０ｍｍｏｌ）の溶液に、イミダゾール（１．１７ｇ、１７．０ｍｍｏｌ）及びｔ－ブチルジメチルシリルクロリド（２．０９ｇ、１３．６ｍｍｏｌ）を順に氷浴上で添加した。系が安定した後、混合物をｒｔに移し、２時間撹拌した。反応を停止し、吸引濾過により濾過し、濾過ケークをＤＣＭ（１０ｍＬ）で洗浄した。濾液を真空濃縮して溶媒を除去し、残分をシリカゲルカラムクロマトグラフィー（ＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ）＝１０／１）で精製して、標題化合物を無色の油として得た（３．２０ｇ、９４．８％）。 Example 22: 2- [1- [2-[[(2S, 3aS, 6aR) -4,5-dihydroxy-1,2,3,3a,4,5,6,6a-octahydropentalene-2- Il] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2 -Methyl-propanoic acid

Step 1) [2-[[(3aR, 6aS) -5-benzyloxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2-( 2-Methoxyphenyl) ethoxy] -t-butyl-dimethylsilane 2-[[(3aR, 6aS) -5-benzyloxy-1,2,3,3a, 4,5,6a] in DCM (30 mL) -Octahydropentalene-2-yl] oxy] -2- (2-methoxyphenyl) in a solution of ethanol (2.60 g, 6.80 mmol) with imidazole (1.17 g, 17.0 mmol) and t-butyldimethyl. Cyril chloride (2.09 g, 13.6 mmol) was added sequentially on an ice bath. After the system was stable, the mixture was transferred to rt and stirred for 2 hours. The reaction was stopped, filtered by suction filtration and the filtration cake was washed with DCM (10 mL). The filtrate was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 10/1) to give the title compound as a colorless oil (3.20 g). , 94.8%).

Step 2) (3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -1,2,3,3a, 4,5,6 6a-Octahydropentalene-2-ol [2-[[(3aR, 6aS) -5-benzyloxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl ] Oxy] -2- (2-methoxyphenyl) ethoxy] -t-butyldimethylsilane (3.20 g, 6.44 mmol) was dissolved in methanol (20 mL) and tetrahydrofuran (10 mL), followed by palladium carbon (0. 32 g, 10%) was added. The mixture was stirred at rt under H ₂ for 2 hours. The mixture was filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a colorless oil (2.62 g, 100%).

Step 3) [(3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -1,2,3,3a, 4,5,6 , 6a-Octahydropentalene-2-yl] Mesylate (3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy in acetone (30 mL) ] -1,2,3,3a,4,5,6,6a-octahydropentalene-2-ol (2.62 g, 6.44 mmol) and triethylamine (3 mL, 21.4 mmol) in a solution of methylsulfonyl. Chloride (1 mL, 12.9 mmol) was slowly added dropwise on an ice bath. The mixture was stirred at rt overnight. The mixture is filtered by suction filtration, the filtrate is vacuum concentrated to remove the solvent and the residue is purified by silica gel column chromatography (PE / EtOAc (V / V) = 4/1) to make the title compound colorless. Obtained as oil (1.884 g, 60.3%).

MS (ESI, pose.ion) m / z: 507.3 [M + Na] ⁺ .

Step 4) [2-[[(2S, 3aR, 6aS) -1,2,3,3a, 4,6a-hexahydropentalene-2-yl] oxy] -2- (2-methoxyphenyl) ethoxy] -T-Butyl-Dimethylsilane [(3aR, 6aS) -5- [2- [t-Butyl (dimethyl) Cyril] Oxy-1- (2-Methoxyphenyl) ethoxy] -1,2 in toluene (20 mL) , 3,3a, 4,5,6,6a-octahydropentalene-2-yl] in a solution of mesylate (1.88 g, 3.88 mmol) with 1,8-diazabicyclo [5.4.0] -7. -Undecene (1.2 mL, 12.9 mmol) was slowly added dropwise at rt. The mixture was stirred at 120 ° C. overnight. The mixture was cooled to rt, adjusted to pH about 5 with dilute hydrochloric acid (2N) and extracted with ethyl acetate (100 mL). The organic phase was washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 10/1) to give the title compound as a colorless oil (0.693 g, 46.0%).

MS (ESI, pose.ion) m / z: 411.1 [M + Na] ⁺ .

Step 5) 2-[[(2S, 3aR, 6aS) -1,2,3,3a, 4,6a-hexahydropentalene-2-yl] oxy] -2- (2-methoxyphenyl) ethanol [2 -[[(2S, 3aR, 6aS) -1,2,3,3a, 4,6a-hexahydropentalene-2-yl] oxy] -2- (2-methoxyphenyl) ethoxy] -t-butyl- Dimethylsilane (0.693 g, 1.78 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of a solution of tetrabutylammonium fluoride (1 mmol / L) in tetrahydrofuran (2.7 mL, 2.7 mmol). The mixture was stirred at rt for 3 hours. The reaction mixture was concentrated in vacuum to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 10/1) to give the title compound as a colorless oil (0. 334 g, 68.3%).

MS (ESI, pose.ion) m / z: 297.1 [M + Na] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.40 (dd, J = 7.5, 1.4 Hz, 1H), 7.30-7.24 (m, 1H), 6.99 (t, J = 7) .4Hz, 1H), 6.87 (d, J = 8.2Hz, 1H), 5.79-5.74 (m, 1H), 5.68-5.64 (m, 1H), 4.92 (Dd, J = 9.0, 3.1Hz, 1H) 3.90-3.85 (m, 1H), 3.84 (s, 3H), 3.66-3.59 (m, 1H) 3,43-3.34 (m, 1H), 3.22-3.15 (m, 1H), 2.78-2.64 (m, 2H), 2.64-2.55 (m,) 1H), 2.41-2.33 (m, 1H), 2.00-1.90 (m, 1H), 1.89-1.82 (m, 1H), 1.79-1.71 ( m, 1H), 1.69-1.65 (m, 1H).

Step 6) 2- [1- [2-[[(2S, 3aR, 6aS) -1,2,3,3a, 4,6a-hexahydropentalene-2-yl] oxy] -2- (2-) Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionate t-butyl (diphenyl) ) 2-[[(2S, 3aR, 6aS) -1,2,3,3a, 4,6a-hexahydropentalene-2-yl] oxy] -2- (2- (2-) in silyl anhydrous tetrahydrofuran (6 mL) Methoxyphenyl) ethanol (0.147 g, 0.536 mmol), 2-methyl-2- (5-methyl-6-oxazol-2-yl-2,4-dioxo-1H-thieno [2,3-d] pyrimid In a solution of t-butyl (diphenyl) silyl (0.338 g, 0.589 mmol) of -3-yl) -propionate and triphenylphosphine (0.287 g, 1.07 mmol), diisopropyl azodicarboxylate (0.22 mL, 0.22 mL, 1.10 mmol) was slowly added dropwise under N ₂ . After the addition, the mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 9/1) to give the title compound as a white solid (0. 346 g, 77.8%).

Step 7) 2- (1- (2- (2-Methoxyphenyl) -2-(((1bS, 3S, 4aS) -octahydropentalene [1,2-b] epoxybin-3-yl) oxy) Ethyl) -5-Methyl-6- (oxazol-2-yl) -2,4-dioxo-1,2-dihydrothieno [2,3-d] pyrimido-3 (4H) -yl) -2-methylpropionic acid 2- [1- [2-[[(2S, 3aR, 6aS) -1,2,3,3a, 4,6a-hexahydropentalene-2-] in t-butyl (diphenyl) silyl DCM (6 mL) Il] Oxy] -2- (2-methoxyphenyl) ethyl) -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2 To a solution of t-butyl (diphenyl) silyl (0.346 g, 0.417 mmol) of -methyl-propionic acid, 3-chloroperoxybenzoic acid (0.089 g, 0.44 mmol) was added at rt. The mixture was stirred for 6 hours. The reaction was quenched with saturated sodium thiosulfate solution (20 mL). The organic layer was washed successively with saturated aqueous sodium bicarbonate solution (20 mL) and saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 5/1) to give the title compound as a white solid (0.276 g, 78.3%).

Step 8) 2- [1- [2-[[(2S, 3aS, 6aR) -4,5-dihydroxy-1,2,3,3a,4,5,6,6a-octahydropentalene-2- Il] Oxy] -2- (2-Methoxyphenyl) Ethyl] -5-Methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2 -Methyl-propanoic acid 2- (1- (2- (2-Methoxyphenyl) -2-(((1bS, 3S, 4aS) -octahydropentalene [1,2-b] epoxy) in tetrahydrofuran (4 mL) Bin-3-yl) Oxy) Ethyl) -5-Methyl-6- (Oxazole-2-yl) -2,4-dioxo-1,2-dihydrothieno [2,3-d] Pyrimid-3 (4H)- Dilute sulfuric acid (1.2 mL, 3 mol / L) was added to a solution of t-butyl (diphenyl) silyl (0.276 g, 0.326 mmol) -2-methylpropionate at rt. The mixture was stirred at 40 ° C. overnight. The mixture was concentrated and water was added to the residue. The solid settled. The mixture was filtered by suction filtration and the filter cake was washed with water (10 mL) and purified by pre-HPLC to give the title compound as a white solid (0.035 g, 17%).

MS (ESI, pose.ion) m / z: 626.3 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ12.38 (s, 1H), 8.21 (s, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.38 (s, 1H), 7.34-7.27 (m, 1H), 7.07-6.96 (m, 2H), 5.20-5.13 (m, 1H), 4.54-4.44 (m, 1H) m, 2H), 3.83 (s, 3H), 3.80-3.75 (m, 1H), 3.69-3.63 (m, 1H), 3.62-3.58 (m, 1H), 2.76 (s, 3H), 2.25-2.15 (m, 1H), 2.04-1.95 (m, 2H), 1.93-1.86 (m, 1H) 1.85-1.76 (m, 1H), 1.74-1.70 (m, 1H), 1.68 (s, 3H), 1.64 (s, 3H), 1.49-1 .37 (m, 2H), 1.37-1.26 (m, 2H).

工程１）（３ａＲ，６ａＳ）－５－［２－［ｔ－ブチル（ジメチル）シリル］オキシ－１－（２－メトキシフェニル）エトキシ］－２－シクロプロピル－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オール
無水テトラヒドロフラン（２０ｍＬ）中の（３ａＲ，６ａＳ）－５－［２－［ｔ－ブチル（ジメチル）シリル］オキシ－１－（２－メトキシフェニル）エトキシ］－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オン（４００ｍｇ、０．９９ｍｍｏｌ）の溶液に、テトラヒドロフラン中のシクロプロピルマグネシウムブロミド（３．０ｍＬ、３．０ｍｍｏｌ、１ｍｏｌ／Ｌ）の溶液をＮ_２下、氷浴上で滴下した。滴下の後、混合物をｒｔで２１時間撹拌した。混合物を水（２ｍＬ）により氷浴上でクエンチした。得られた混合物を酢酸エチル（３０ｍＬ×２）で抽出した。併せた有機相を無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮した。残分をシリカゲルクロマグラフィー（ＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ）＝４／１）で精製して、標題化合物を淡黄色の油として得た（１９８ｍｇ、４４．８％）。 Example 23: 2- [1- [2-[[(3aR, 6aS) -5-cyclopropyl-5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl]] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl -Propyl acid

Step 1) (3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -2-cyclopropyl-3,3a, 4,5,6 , 6a-Hexahydro-1H-pentalene-2-ol (3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy in anhydrous tetrahydrofuran (20 mL) ] -3,3a, 4,5,6,6a-Hexahydro-1H-pentalene-2-one (400 mg, 0.99 mmol) in a solution of cyclopropyl magnesium bromide (3.0 mL, 3.0 mmol) in tetrahydrofuran, A solution of 1 mol / L) was added dropwise on an ice bath under _N2 . After the dropping, the mixture was stirred at rt for 21 hours. The mixture was quenched on an ice bath with water (2 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 4/1) to give the title compound as a pale yellow oil (198 mg, 44.8%).

MS (ES / API, pos.ion) m / z: 469.4 [M + Na] ⁺ .

Step 2) (3aR, 6aS) -2-Cyclopropyl-5- [2-Hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-Hexahydro-1H-pentalene- (3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -2-cyclopropyl-3, in 2-ol anhydrous tetrahydrofuran (10 mL), A solution of tetrabutylammonium fluoride (1 mol / L) in tetrahydrofuran (0.9 mL, 0.9 mL,) to a solution of 3a, 4,5,6,6a-hexahydro-1H-pentalene-2-ol (198 mg, 0.44 mmol). 0.9 mmol) was added at rt. After the addition, the mixture was stirred for 1 hour. The mixture was concentrated to remove most of the solvent. Water (50 mL) was added to the residue to quench the reaction, the mixture was extracted with EtOAc (30 mL × 2) and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (V / V = 3/1)) to give the title compound as a white solid (125 mg, 84.8%).

MS (ES / API, pos.ion) m / z: 355.3 [M + Na] ⁺ .

Step 3) 2- [1- [2-[[(3aR, 6aS) -5-cyclopropyl-5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl]] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl -(3aR, 6aS) -2-cyclopropyl-5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, in t-butyl (diphenyl) silyl anhydrous tetrahydrofuran (10 mL) of propionate, 4,5,6,6a-Hexahydro-1H-pentalene-2-ol (121 mg, 0.36 mmol), 2-methyl-2- (5-methyl-6-oxazole-2-yl-2,4-dioxo-) Azodicarboxylic in a solution of 1H-thieno [2,3-d] pyrimido-3-yl) -propionic acid t-butyl (diphenyl) silyl (200 mg, 0.35 mmol) and triphenylphosphine (184 mg, 0.69 mmol). It was slowly added dropwise under diisopropyl acid (143 mg, 0.69 mmol) N ₂ . After the dropping, the mixture was stirred for 21 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 4/1) to give the title compound as a grayish white solid (245 mg, 97.1%).

Step 4) 2- [1- [2-[[(3aR, 6aS) -5-cyclopropyl-5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl]] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl -Propyl acid 2- [1- [2-[[(3aR, 6aS) -5-cyclopropyl-5-hydroxy-2,3,3a, 4,6,6a-hexahydro- in tetrahydrofuran (2.0 mL)) 1H-pentalene-2-yl) oxy) -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido- 3-Il] In a solution of t-butyl (diphenyl) silyl (245 mg, 0.27 mmol) -2-methyl-propionate, a solution of tetrabutylammonium fluoride in tetrahydrofuran (0.8 mL, 0.8 mmol, 1 mol / mol / L) was added by rt. The mixture was stirred for 2 hours. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The resulting mixture was dispensed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound as a white solid (52 mg, 29.0%).

MS (ES / API, neg.ion) m / z: 648.3 [MH] ^{-
1 1} H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.54-7.52 (m, 1H), 7.31-7.26 (m, 1H), 7.21 (s, 1H), 7.01 (t, J = 7.4Hz, 1H), 6.87 (d, J = 8.2Hz, 1H) 5.29-5.26 (m, 1H) 4.32- 4.26 (m, 1H), 3.99-3.93 (m, 1H), 3.89 (s, 3H), 3.76-3.68 (m, 1H), 2.84 (s, 3H), 2.31-2.27 (m, 2H), 2.02-1.91 (m, 2H), 1.86 (s, 3H), 1.83 (s, 3H), 1.77 -1.66 (m, 3H), 1.57-1.51 (m, 3H), 1.00-0.93 (m, 1H), 0.37-0.31 (m, 2H), 0 .28-0.25 (m, 2H).

例１に記載の方法に従って２－［２－（ジフルオロメトキシ）フェニル］酢酸（３．００ｇ、１４．８ｍｍｏｌ）から標題化合物を調製した。標題化合物を灰色の固体として得た（０．８０ｇ、８．４％）。 Example 24: 2- [1- [2-[[(3aR, 6aS) -5-hydroxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- [2- (Difluoromethoxy) phenyl] ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2- Methyl-propanoic acid

The title compound was prepared from 2- [2- (difluoromethoxy) phenyl] acetic acid (3.00 g, 14.8 mmol) according to the method described in Example 1. The title compound was obtained as a gray solid (0.80 g, 8.4%).

MS (ESI, neg.ion) m / z: 644.3 [MH] ^- ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.72 (d, J = 5.9 Hz, 1H), 7.62 (d, J = 6.1 Hz, 1H), 7.35 (t, J = 9.5 Hz) , 1H), 7.31 (t, J = 8.1Hz, 1H), 7.24 (s, 1H), 7.19 (d, J = 7.7Hz, 1H), 6.71 (d, J) = 2.2Hz, 1H), 5.32-5.28 (m, 1H), 4.25-4.16 (m, 2H), 4.07 (d, J = 12.9Hz, 1H), 3 .81-3.77 (m, 1H), 2.86 (s, 3H), 2.30-2.20 (m, 2H), 1.94-1.90 (m, 2H), 1.85 (S, 3H), 1.81 (s, 3H), 1.71-1.64 (m, 2H), 1.64-1.56 (m, 2H), 1.52-1.50 (m) , 1H), 1.49-1.47 (m, 1H).

工程１）２－［（３ａＲ，６ａＳ）－５－［２－［ｔ－ブチル（ジメチル）シリル］オキシ－１－（２－メトキシフェニル）エトキシ］－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－イリデン］アセトニトリル
テトラヒドロフラン（２０．０ｍＬ）中のシアノメチルリン酸ジメチル（１９７ｍｇ、１．１１ｍｍｏｌ）の溶液をＮ_２下で－２０℃まで冷却した。溶液にｎ－ヘキサン中のｎ－ブチルリチウムの溶液（０．９ｍＬ、２．０ｍｍｏｌ、２．５ｍｏｌ／Ｌ）を滴下した。滴下の後、混合物をｒｔで３０分間撹拌した。溶液にテトラヒドロフラン（１．０ｍＬ）中の（３ａＳ，６ａＲ）－５－［２－［ｔ－ブチル（ジメチル）シリル］オキシ－１－（２－メトキシフェニル）エトキシ］－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オン（３００ｍｇ、０．７４ｍｍｏｌ）の溶液を０℃で滴下した。滴下の後、混合物をｒｔで２１時間撹拌した。混合物を水（１０．０ｍＬ）によって０℃でクエンチした。得られた混合物を酢酸エチル（３０ｍＬ×２）で抽出した。併せた有機相を無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮して、標題化合物を淡黄色の油として得た（３１０ｍｇ、９７．８％）。 Example 25: 2- [1- [2-[[(3aS, 6aR) -5- (cyanomethyl) -1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl]] Oxy] -2- (2-methoxyphenyl) ethyl) -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl -Propionic acid

Step 1) 2-[(3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,66a -Hexahydro-1H-pentalene-2-iriden] acetonitrile A solution of dimethyl cyanomethylphosphate (197 mg, 1.11 mmol) in acetonitrile (20.0 mL) was cooled to −20 ° C. under _N2 . A solution of n-butyllithium in n-hexane (0.9 mL, 2.0 mmol, 2.5 mol / L) was added dropwise to the solution. After the dropping, the mixture was stirred at rt for 30 minutes. (3aS, 6aR) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5 in tetrahydrofuran (1.0 mL) in solution , 6,6a-Hexahydro-1H-pentalene-2-one (300 mg, 0.74 mmol) solution was added dropwise at 0 ° C. After the dropping, the mixture was stirred at rt for 21 hours. The mixture was quenched with water (10.0 mL) at 0 ° C. The resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (310 mg, 97.8%).

MS (ES / API, pose.ion) m / z: 314.3 [M-TBS + H] ⁺ .

Step 2) 2-[(3aS, 6aR) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -1,2,3,3a, 4,5 , 6,6a-Octahydropentalene-2-yl] acetonitrile 2-[(3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-hexahydro-1H-pentalene-2-iriden] acetonitrile (310 mg, 0.72 mmol) was dissolved in methanol (10.0 mL), followed by palladium carbon (31 mg, 0). .29 mmol, 10%) was added. The gas of the system was replaced with H ₂ three times and the mixture was stirred at rt under H ₂ for 30 minutes. The mixture was filtered. The filter cake was washed with methanol (10 mL). The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (310 mg, 99.5%).

MS (ES / API, pos.ion) m / z: 452.4 [M + Na] ⁺ .

Step 3) 2-[(3aS, 6aR) -5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -1,2,3,3a, 4,5,6,6a-octahydropentalene -2-Il] acetonitrile 2-[(3aS, 6aR) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -1 in anhydrous tetrahydrofuran (10 mL) , 2,3,3a,4,5,6,6a-octahydropentalene-2-yl] A solution of tetrabutylammonium fluoride in tetrahydrofuran (2.1 mL) in a solution of acetonitrile (310 mg, 0.72 mmol). , 2.0 mmol, 1.0 mol / L) was added at rt. After the addition, the mixture was stirred for 30 minutes. The mixture was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 4/1) to give the title compound as a white solid (120 mg, 80.7%).

MS (ES / API, pose.ion) m / z: 316.3 [M + H] ⁺ .

Step 4) 2- [1- [2-[[(3aS, 6aR) -5- (cyanomethyl) -1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl -T-Butyl (diphenyl) silyl chloride of propionate 2-[(3aS, 6aR) -5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -1,2,3 in anhydrous tetrahydrofuran (10 mL) 3a, 4,5,6,6a-octahydropentalene-2-yl] acetonitrile (115 mg, 0.36 mmol), 2-methyl-2- (5-methyl-6-oxazole-2-yl-2,4) -Dioxo-1H-thieno [2,3-d] pyrimido-3-yl) -propionic acid t-butyl (diphenyl) silyl (200 mg, 0.35 mmol) and triphenylphosphine (184 mg, 0.69 mmol) in a solution. , Azodicarboxylate diisopropyl (144 mg, 0.69 mmol) N ₂ was slowly added dropwise. After the dropping, the mixture was stirred for 2.5 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 6/1) to give the title compound as a grayish white solid (200 mg, 65.8%).

Step 5) 2- [1- [2-[[(3aS, 6aR) -5- (cyanomethyl) -1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] Oxy] -2- (2-methoxyphenyl) ethyl) -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl -Proanoic acid 2- [1- [2-[[(3aS, 6aR) -5- (cyanomethyl) -1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl -T-butyl (diphenyl) silyl (200 mg, 0.23 mmol) of propionate was dissolved in tetrahydrofuran (20 mL). A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mol / L, 0.7 mL, 0.7 mmol) was added to the mixture at rt. The mixture was stirred at rt for 1.5 hours. The mixture was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 1/1) to give the title compound as a grayish white solid (12 mg, 8.3%).

MS (ES / API, pose.ion) m / z: 633.1 [M + H] ^{+
1 1} H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.28-7.22 (m, 2H), 7.01 ( t, J = 7.4Hz, 1H), 6.82 (d, J = 8.2Hz, 1H), 5.30-5.27 (m, 1H), 4.09-4.04 (m, 2H) ), 3.86-3.82 (m, 1H), 3.80 (s, 3H), 2.84 (s, 3H), 2.37-2.29 (m, 2H), 2.25- 2.20 (m, 1H), 2.09-1.98 (m, 3H), 1.93-1.86 (m, 2H), 1.84 (s, 3H), 1.81 (s, 3H), 1.41-1.33 (m, 2H), 1.17-1.04 (m, 3H).

工程１）（３ａＲ，６ａＳ）－５－［２－ヒドロキシ－１－（２－メトキシフェニル）エトキシ］－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オン
無水テトラヒドロフラン（１０ｍＬ）中の（３ａＳ，６ａＲ）－５－［２－［ｔ－ブチル（ジメチル）シリル］オキシ－１－（２－メトキシフェニル）エトキシ］－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オン（１．００ｇ、２．５０ｍｍｏｌ）の溶液に、テトラヒドロフラン中のフッ化テトラブチルアンモニウム（１ｍｏｌ／Ｌ）の溶液（３．７ｍＬ、３．７０ｍｍｏｌ）をｒｔで添加した。添加の後、混合物を４０分間撹拌した。混合物を濃縮して溶媒を除去した。残分に、水（１００ｍＬ）及びＥｔＯＡｃ（１００ｍＬ）を添加し、混合物を分配した。有機層を無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮した。残分をシリカゲルカラムクロマトグラフィー（ＤＣＭ／ＥｔＯＡｃ（Ｖ／Ｖ＝１０／１）で精製して、標題化合物を白色の固体として得た（０．５２ｇ、７０％）。 Example 26: 2- [1- [2-[[(3aR, 6aS) -5-cyano-5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- Propanic acid

Step 1) (3aR, 6aS) -5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-hexahydro-1H-pentalene-2-one anhydrous tetrahydrofuran (3aS, 6aR) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6a- in (10 mL) A solution of tetrabutylammonium fluoride (1 mol / L) in tetrahydrofuran (3.7 mL, 3.70 mmol) was added to a solution of hexahydro-1H-pentalene-2-one (1.00 g, 2.50 mmol) at rt. did. After the addition, the mixture was stirred for 40 minutes. The mixture was concentrated to remove the solvent. Water (100 mL) and EtOAc (100 mL) were added to the residue and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / EtOAc (V / V = 10/1)) to give the title compound as a white solid (0.52 g, 70%).

MS (ES / API, pos.ion) m / z: 313.1 [M + Na] ⁺ .

Step 2) (3aR, 6aS) -2-Hydroxy-5- [2-Hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-Hexahydro-1H-pentalene-2 -Carbonitrile (3aR, 6aS) -5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-hexahydro-1H- in anhydrous tetrahydrofuran (10 mL) A solution of trimethylsilyl cyanide (0.85 mL, 6.2 mmol) and tetrabutylammonium fluoride in tetrahydrofuran (6.0 mL, 6.0 mmol, 1 mol / mmol) in a solution of pentalen-2-one (900 mg, 3.10 mmol). L) was added in order under N ₂ at rt. After the addition, the mixture was stirred at rt for 15 hours. The reaction was quenched with dilute hydrochloric acid (1 mL, 2N). The mixture was concentrated to remove most of the solvent. Water (20 mL) and EtOAc (20 mL) were added to the residue and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (V / V = 3/1)) to give the title compound as a white solid (190 mg, 19.32%).

MS (ES / API, pose.ion) m / z: 318.3 [M + H] ^{+
1 1} H NMR (400 MHz, CD ₃ OD) δ7.31-7.35 (m, 1H), 7.28-7.21 (m, 1H), 6.91-6.98 (m, 2H), 3 .96-3.89 (m, 1H), 3.84 (m, 3H), 3.56-3.43 (m, 2H), 2.87-2.71 (m, 2H), 2.63 -2.46 (m, 2H), 2.41-2.32 (m, 1H), 2.23-2.27 (m, 1H), 2.10-1.95 (m, 2H), 1 .80-1.84 (m, 1H), 1.67-1.58 (m, 1H).

Step 3) 2- [1- [2-[[(3aR, 6aS) -5-cyano-5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- (3aR, 6aS) -2-hydroxy-5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4, in anhydrous tetrahydrofuran (10 mL) t-butyl (diphenyl) propionate 5,6,6a-Hexahydro-1H-pentalene-2-carbonitrile (91 mg, 0.29 mmol), 2-methyl-2- (5-methyl-6-oxazole-2-yl-2,4-dioxo-1H) -Azodicarboxylic acid in a solution of thieno [2,3-d] pyrimido-3-yl) -propionic acid t-butyl (diphenyl) silyl (150 mg, 0.26 mmol) and triphenylphosphine (105 mg, 0.39 mmol). Diisopropyl (0.08 mL, 0.40 mmol) was slowly added dropwise under _N2 . After the addition, the mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 2/1) to give the title compound as a white solid (228 mg, 99.9%).

Step 4) 2- [1- [2-[[(3aR, 6aS) -5-cyano-5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- 2- [1- [2-[[(3aR, 6aS) -5-cyano-5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-" in tetrahydrofuran (6 mL) of propanoic acid 2-Il) Oxy) -2- (2-Methoxyphenyl) Ethyl] -5-Methyl-6-Oxazole-2-yl-2,4-dioxo-thieno [2,3-d] Pyrimid-3-yl] A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.4 mL, 0.4 mmol, 1 mol / L) was added to a solution of t-butyl (diphenyl) silyl (228 mg, 0.26 mmol) of -2-methyl-propionate. Was added in. The mixture was stirred for 30 minutes. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with (DCM / MeOH (V / V) = 8/1) to give the title compound as a white solid (40 mg, 24%).

MS (ES / API, pos.ion) m / z: 635.0 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.71 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.32-7.25 (m, 1H), 7.23 ( s, 1H), 7.04 (t, J = 7.4Hz, 1H), 6.84 (d, J = 8.1Hz, 1H), 5.31 (dd, J = 8.8, 4.6Hz) , 1H), 4.12-4.06 (m, 2H), 4.00-3.88 (m, 1H), 3.82 (s, 3H), 2.86 (s, 3H), 2. 68-2.59 (m, 2H), 2.50-2.42 (m, 1H), 2.41-2.33 (m, 1H), 2.20-1.11 (m, 1H), 2.09-1.97 (m, 3H), 1.88 (s, 3H), 1.84 (s, 3H), 1.64-1.59 (m, 1H), 1.58-1. 52 (m, 1H).

工程１）２－［（３ａＳ，６ａＲ）－５－［２－［ｔ－ブチル（ジメチル）シリル］オキシ－１－（２－メトキシフェニル）エトキシ］－２－ヒドロキシ－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－イル］アセトニトリル
アセトニトリル（５．０ｍＬ）をＮ_２下で－７８℃まで冷却した。溶液に、ｎ－ヘキサン中のｎ－ブチルリチウムの溶液（０．３ｍＬ、０．８ｍｍｏｌ、２．５ｍｏｌ／Ｌ）を滴下した。滴下の後、混合物を１０分間撹拌し、更にｒｔで３０分間撹拌した。系に、アセトニトリル（１．０ｍＬ）中の（３ａＳ，６ａＲ）－５－［２－［ｔ－ブチル（ジメチル）シリル］オキシ－１－（２－メトキシフェニル）エトキシ］－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オン（１００ｍｇ、０．２５ｍｍｏｌ）の溶液を－７８℃で滴下した。滴下の後、混合物をｒｔで１９時間撹拌した。混合物を水（１０．０ｍＬ）によって－１０℃でクエンチした。得られた混合物を酢酸エチル（２０ｍＬ×２）で抽出した。併せた有機相を無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮した。残分をシリカゲルクロマグラフィー（ＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ）＝４／１）で精製して、標題化合物を淡黄色の油として得た（３５ｍｇ、３１．８％）。 Example 27: 2- [1- [2-[[(3aS, 6aR) -5- (cyanomethyl) -5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl ] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2- Methyl-propanoic acid

Step 1) 2-[(3aS, 6aR) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -2-hydroxy-3,3a, 4,5 , 6,6a-Hexahydro-1H-pentalene-2-yl] acetonitrile Acetonitrile (5.0 mL) was cooled to −78 ° C. under _N2 . A solution of n-butyllithium in n-hexane (0.3 mL, 0.8 mmol, 2.5 mol / L) was added dropwise to the solution. After the dropping, the mixture was stirred for 10 minutes and then at rt for 30 minutes. In the system, (3aS, 6aR) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4, in acetonitrile (1.0 mL) A solution of 5,6,6a-hexahydro-1H-pentalene-2-one (100 mg, 0.25 mmol) was added dropwise at −78 ° C. After the dropping, the mixture was stirred at rt for 19 hours. The mixture was quenched with water (10.0 mL) at −10 ° C. The resulting mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 4/1) to give the title compound as a pale yellow oil (35 mg, 31.8%).

MS (ES / API, pos.ion) m / z: 468.4 [M + Na] ⁺ .

Step 2) 2-[(3aS, 6aR) -2-hydroxy-5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6a-6a-hexahydro-1H- Pentalene-2-yl] acetonitrile 2-[(3aS, 6aR) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy]-in anhydrous tetrahydrofuran (10 mL) 2-Hydroxy-3,3a, 4,5,6,6a-hexahydro-1H-pentalene-2-yl] In a solution of acetonitrile (200 mg, 0.45 mmol), tetrabutylammonium fluoride (1 mol / L) in tetrahydrofuran is added. ) Solution (1.4 mL, 1.4 mol / L) was added at rt. After the addition, the mixture was stirred for 17 hours. The mixture was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 1/1) to give the title compound as a white solid (120 mg, 80.7%).

MS (ES / API, pos.ion) m / z: 332.3 [M + Na] ⁺ .

Step 3) 2- [1- [2-[[(3aS, 6aR) -5- (cyanomethyl) -5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl ] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2- 2-[(3aS, 6aR) -2-hydroxy-5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy]-in methyl-propionic acid t-butyl (diphenyl) silyl anhydrous tetrahydrofuran (10 mL) 3,3a, 4,5,6,6a-hexahydro-1H-pentalene-2-yl] acetonitrile (120 mg, 0.36 mmol), 2-methyl-2- (5-methyl-6-oxazole-2-yl-) 2,4-Dioxo-1H-thieno [2,3-d] pyrimido-3-yl) -t-butyl (diphenyl) silyl (200 mg, 0.35 mmol) -propionate and triphenylphosphine (184 mg, 0.69 mmol) Was slowly added dropwise to the solution of diisopropyl azodicarboxylate (143 mg, 0.69 mmol) under _N2 . After the dropping, the mixture was stirred for 18 hours. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 4/1) to give the title compound as a grayish white solid (240 mg, 77.6%).

Step 4) 2- [1- [2-[[(3aS, 6aR) -5- (cyanomethyl) -5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-2-yl ] Oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2- Methyl-propanoic acid 2- [1- [2-[[(3aS, 6aR) -5- (cyanomethyl) -5-hydroxy-2,3,3a, 4,6,6a-hexahydro- in tetrahydrofuran (20 mL)) 1H-pentalene-2-yl] oxy] -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido- 3-Il] A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.8 mL, 0.8 mmol, 1 mol / mol /) in a solution of t-butyl (diphenyl) silyl (240 mg, 0.27 mmol) -2-methyl-propionate. L) was added at rt. The mixture was stirred for 4.5 hours. The mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (EtOAc) to give the title compound as a white solid (59 mg, 27%).

MS (ES / API, pose.ion) m / z: 649.3 [M + H] ^{+
1 1} H NMR (400 MHz, CDCl ₃ ) δ7.71 (s, 1H), 7.46 (d, J = 6.5 Hz, 1H), 7.31-7.26 (m, 2H), 7.00 ( t, J = 7.4Hz, 1H), 6.87 (d, J = 8.2Hz, 1H), 5.31-5.28 (m, 1H), 4.37-4.23 (m, 1H) ), 4.07-4.01 (m, 1H), 3.89 (s, 3H), 3.83-3.76 (m, 1H), 2.82 (s, 3H), 2.54 ( s, 2H), 2.46-2.34 (m, 2H), 2.02-1.97 (m, 1H), 1.94-1.89 (m, 2H), 1.87-1. 83 (m, 2H), 1.81 (s, 3H), 1.80 (s, 3H), 1.78-1.57 (m, 3H).

工程１）（３ａＲ，６ａＳ）－５－［２－［ｔ－ブチル（ジメチル）シリル］オキシ－１－（２－メトキシフェニル）エトキシ］－２－エチル－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オール
無水テトラヒドロフラン（５ｍＬ）中の（３ａＳ，６ａＲ）－５－［２－［ｔ－ブチル（ジメチル）シリル］オキシ－１－（２－メトキシフェニル）エトキシ］－３，３ａ，４，５，６，６ａ－ヘキサヒドロ－１Ｈ－ペンタレン－２－オン（６５０ｍｇ、１．６０７ｍｍｏｌ）の溶液に、ｎ－ヘキサン中のｎ－ブチルリチウムの溶液（１．２ｍＬ、３．０ｍｍｏｌ、２．５ｍｏｌ／Ｌ）をＮ_２下、氷浴上で滴下した。滴下の後、混合物を４時間撹拌した。反応物を飽和含水塩化アンモニウム（３ｍＬ）でクエンチした。混合物を濃縮して溶媒の大半を除去した。残分に、水（５０ｍＬ）及びＥｔＯＡｃ（５０ｍＬ）を添加し、混合物を分配した。有機層を無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮して、標題化合物を無色の油として得た（４１０ｍｇ、５５．１６％）。 Example 28: 2- [1- [2-[[(3aR, 6aS) -5-butyl-5-hydroxy-2,3,3a,4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- Propanic acid

Step 1) (3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -2-ethyl-3,3a, 4,5,6 (3aS, 6aR) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] in 6a-hexahydro-1H-pentalene-2-ol anhydrous tetrahydrofuran (5 mL) A solution of n-butyllithium in n-hexane (1.2 mL, 3) in a solution of -3,3a, 4,5,6,6a-hexahydro-1H-pentalene-2-one (650 mg, 1.607 mmol). 9.0 mmol (2.5 mol / L) was added dropwise on an ice bath under N ₂ . After the dropping, the mixture was stirred for 4 hours. The reaction was quenched with saturated aqueous ammonium chloride (3 mL). The mixture was concentrated to remove most of the solvent. Water (50 mL) and EtOAc (50 mL) were added to the residue and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a colorless oil (410 mg, 55.16%).

Step 2) (3aR, 6aS) -2-Butyl-5- [2-Hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4,5,6,6a-Hexahydro-1H-pentalene-2 -(3aR, 6aS) -5- [2- [t-butyl (dimethyl) silyl] oxy-1- (2-methoxyphenyl) ethoxy] -2-ethyl-3,3a in all anhydrous tetrahydrofuran (10 mL), A solution of tetrabutylammonium fluoride (1 mol / L) in tetrahydrofuran (1.0 mL, 1.) in a solution of 4,5,6,6a-hexahydro-1H-pentalene-2-ol (410 mg, 0.886 mmol). 0 mmol) was added in rt. After the addition, the mixture was stirred for 1 hour. The mixture was concentrated to remove most of the solvent. Water (50 mL) and EtOAc (50 mL) were added to the residue and the mixture was dispensed. The organic layer was dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / EtOAc (V / V = 10/1)) to give the title compound as a colorless oil (230 mg, 74.48%).

MS (ES / API, pos.ion) m / z: 371.3 [M + Na] ⁺ .

Step 3) 2- [1- [2-[[(3aR, 6aS) -5-butyl-5-hydroxy-2,3,3a,4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- (3aR, 6aS) -2-butyl-5- [2-hydroxy-1- (2-methoxyphenyl) ethoxy] -3,3a, 4, in t-butyl (diphenyl) silyl anhydrous tetrahydrofuran (6 mL) propionate 5,6,6a-Hexahydro-1H-pentalene-2-ol (107 mg, 0.307 mmol), 2-methyl-2- (5-methyl-6-oxazole-2-yl-2,4-dioxo-1H-) Diisopropyl azodicarboxylate in a solution of t-butyl (diphenyl) silyl (160 mg, 0.279 mmol) of thieno [2,3-d] pyrimido-3-yl) -propionate and triphenylphosphine (150 mg, 0.56 mmol). (0.12 mL, 0.56 mmol) was slowly added dropwise under _N2 . After the dropping, the mixture was stirred for 19 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 3/1) to give the title compound as a pale yellow oil (252 mg). , 100%).

Step 4) 2- [1- [2-[[(3aR, 6aS) -5-butyl-5-hydroxy-2,3,3a,4,6,6a-hexahydro-1H-pentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- 2- [1- [2-[[(3aR, 6aS) -5-butyl-5-hydroxy-2,3,3a, 4,6,6a-hexahydro-1H-pentalene-" in tetrahydrofuran (5 mL) of propanoic acid 2-yl) oxy) -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.42 mL, 0.42 mmol, 1 mol / L) was added to a solution of t-butyl (diphenyl) silyl (252 mg, 0.279 mmol) of -2-methyl-propionate. Added in. The mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a white solid (35 mg, 19%).

MS (ESI, pose.ion) m / z: 688.1 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.72 (s, 1H), 7.56 (d, J = 6.6 Hz, 1H), 7.33-7.29 (m, 1H), 7.23 ( s, 1H), 7.04 (t, J = 7.4Hz, 1H), 6.90 (d, J = 8.2Hz, 1H), 5.30 (dd, J = 9.1, 3.5Hz) , 1H), 4.36-4.29 (m, 1H), 3.94 (s, 3H), 3.86-3.80 (m, 1H), 3.78-3.70 (m, 1H) , 2.87 (s, 3H), 2.34-2.30 (m, 2H), 2.05-1.95 (m, 4H), 1.91 (s, 3H), 1.85 ( s, 3H), 1.82-1.73 (m, 3H), 1.68-1.55 (m, 4H), 1.53-1.41 (m, 3H), 0.91 (t, J = 6.5Hz, 3H).

工程１）［（３ａＲ，６ａＳ）－５－ベンジルオキシ－１，２，３，３ａ，４，５，６，６ａ－オクタヒドロペンタレン－２－イル］メシレート
アセトン（６０ｍＬ）中の（３ａＲ，６ａＳ）－５－ベンジルオキシ－１，２，３，３ａ，４，５，６，６ａ－オクタヒドロペンタレン－２－オール（４．００ｇ、１７．２ｍｍｏｌ）及びトリエチルアミン（４．９ｍＬ、３５ｍｍｏｌ）の溶液に、メチルスルホニルクロリド（１．７３ｍＬ、２２．４ｍｍｏｌ）ゆっくりと氷浴上で滴下した。混合物をｒｔで３時間撹拌した。反応物を吸引濾過により濾過した。濾液を真空濃縮した。残分を酢酸エチル（８０ｍＬ）に溶解した。混合物を水（５０ｍＬ）及び飽和塩水（５０ｍＬ）で順に洗浄し、無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮して、標題化合物を黄褐色の油として得た（５．３４ｇ、１００％）。この粗生成物を更なる精製をすることなく次の工程に用いた。 Example 29: 2- [1- [2-[[(3aR, 6aS) -5-methylsulfonyl-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- Propionic acid

Step 1) [(3aR, 6aS) -5-benzyloxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] mesylate in acetone (60 mL) (3aR, 6aS) -5-benzyloxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-ol (4.00 g, 17.2 mmol) and triethylamine (4.9 mL, 35 mmol) Methylsulfonyl chloride (1.73 mL, 22.4 mmol) was slowly added dropwise to the solution of the above on an ice bath. The mixture was stirred at rt for 3 hours. The reaction was filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (80 mL). The mixture was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a tan oil (5.34 g, 100%). This crude product was used in the next step without further purification.

Step 2) In (3aR, 6aS) -2-benzyloxy-5-methylthio-1,2,3,3a, 4,5,6,6a-octahydropentalene anhydrous N, N-dimethylformamide (50 mL) [(3aR, 6aS) -5-benzyloxy-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] in a solution of mesylate (5.34 g, 17.2 mmol) , Anhydrous methylmercaptan sodium (1.52 g, 20.6 mmol) was added. The mixture was stirred at 80 ° C. overnight, then cooled to rt, quenched with water (200 mmol) and extracted with ethyl acetate (100 mL). The organic phase was washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 4/1) to give the title compound as a colorless oil (2.00 g, 44.3%).

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.37-7.28 (m, 5H), 4.51 (s, 2H), 3.90-3.81 (m, 1H), 3.27-3. 20 (m, 1H), 2.59-2.52 (m, 2H), 2.21-2.13 (m, 2H), 2.11 (s, 3H), 1.90-1.85 ( m, 2H), 1.75-1.68 (m, 3H), 1.42-1.33 (m, 2H).

Step 3) (3aR, 6aS) (3aR, 6aS) in (3aR, 6aS) -2-benzyloxy-5-methylsulfonyl-1,2,3,3a, 4,5,6,6a-octahydropentalene DCM (20 mL) In a solution of -2-benzyloxy-5-methylthio-1,2,3,3a, 4,5,6,6a-octahydropentalene (1.70 g, 6.48 mmol), 3-chloroperoxybenzoic acid ( 4.50 g, 25.8 mmol) was added in portions on an ice bath under _N2 . The mixture was stirred at rt for 8 hours. The mixture was quenched by dropping a sodium sulfite solution (20 mL) and then a saturated sodium bicarbonate solution (20 mL) was further added. The resulting mixture was extracted with ethyl acetate (120 mL x 2). The combined organic phases were washed with saturated brine (50 mL) and then concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 4/1) to give the title compound as a colorless oil (1.80 g, 94.4%).

Step 4) (3aR, 6aS) (3aR, 6aS) in (3aR, 6aS) -5-methylsulfonyl-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-ol anhydrous methanol (15 mL) Palladium carbon (0.10 g) in a solution of -2-benzyloxy-5-methylsulfonyl-1,2,3,3a, 4,5,6,6a-octahydropentalene (0.80 g, 2.7 mmol). 10%) was added at rt. The mixture was stirred under H2 for ₈ hours. The reaction mixture is filtered by suction filtration, the filtrate is vacuum concentrated to remove solvent and the residue is purified by silica gel column chromatography (PE / EtOAc (V / V) = 1/1) to whiten the title compound. Obtained as a solid of (0.40 g, 72.0%).

Step 5) 2-[[(3aR, 6aS) -5-methylsulfonyl-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2) -Methoxyphenyl) acetic acid (3aR, 6aS) -5-methylsulfonyl-1,2,3,3a,4,5,6,6a-octahydropentalene-2-ol (0. Sodium hydride (0.30 g, 7.5 mmol, 60%) was added to a solution of 40 g, 2.0 mmol) in portions under N ₂ on an ice bath. After stirring for 15 minutes, a solution of 2-bromo-2- (methoxyphenyl) acetic acid (0.50 g, 2.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the mixture. After the addition, the mixture was transferred to rt and stirred for an additional 8 hours. The mixture was quenched by dropping water (30 mL) on an ice bath and the resulting mixture was washed with ethyl acetate (30 mL x 2). The combined aqueous layer was adjusted to pH about 3 with dilute hydrochloric acid (2N) and then extracted with ethyl acetate (30 mL × 2). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (0.70 g, 97.0%). This crude product was used in the next step without further purification.

MS (ESI, neg.ion) m / z: 345.1 [MH] ^- .

Step 6) 2-[[(3aR, 6aS) -5-methylsulfonyl-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] -2- (2) -Methoxyphenyl) ethanol 2-[[(3aR, 6aS) -5-methylsulfonyl-1,2,3,3a, 4,5,6a-6a-octahydropentalene-2-] in anhydrous tetrahydrofuran (10 mL) Lithium aluminum hydride (0.15 g, 4.0 mmol) was partially added to a solution of yl] oxy] -2- (2-methoxyphenyl) acetic acid (2.20 g, 5.63 mmol) on an ice bath. .. After the mixture was stable, the mixture was transferred to rt and stirred for 4 hours. The mixture was quenched by dropping water (0.15 mL) on an ice bath. Sodium hydroxide solution (0.15 mL, 15%) and water (0.45 mL) were then added to the mixture in sequence. The resulting mixture was stirred at rt for a further 15 minutes, anhydrous sodium sulfate was added and the mixture was stirred for a further 15 minutes. The mixture was filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 2/1) to give the title compound as a colorless oil (0.30 g, 45.0%).

MS (ESI, pose.ion) m / z: 355.0 [M + H] ⁺ .

Step 7) 2- [1- [2-[[(3aR, 6aS) -5-methylsulfonyl-1,2,3,3a,4,5,6,6a-octahydropentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- T-butyl (diphenyl) propionate silyl 2-methyl-2- (5-methyl-6-oxazolyl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) propionate t- Butyl (diphenyl) silyl (0.25 g, 0.44 mmol), 2-[[(3aR, 6aS) -5-methylsulfonyl-1,2,3,3a, 4,5,6,6a-octahydropentalene -2-Il] Oxy] -2- (2-Methoxyphenyl) ethanol (0.16 g, 0.45 mmol) and triphenylphosphine (0.25 g, 0.95 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL) with rt. .. Diisopropyl azodicarboxylate (0.21 g, 0.20 mmol) was added to the mixture under N ₂ , and the resulting mixture was stirred at rt for 12 hours and concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 2/1) to give the title compound as a yellow oil (0.15 g, 37.0%).

Step 8) 2- [1- [2-[[(3aR, 6aS) -5-methylsulfonyl-1,2,3,3a, 4,5,6,6a-octahydropentalene-2-yl] oxy] ] -2- (2-Methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl- 2- [1- [2-[[(3aR, 6aS) -5-methylsulfonyl-1,2,3,3a, 4,5,6,6a-octahydropentalene-" in tetrahydrofuran (4 mL) of propanoic acid 2-Il] Oxy] -2- (2-Methoxyphenyl) ethyl] -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] A solution of tetrabutylammonium fluoride in tetrahydrofuran (4 mL, 1 mol / L) was added to a solution of t-butyl (diphenyl) silyl (0.11 g, 0.12 mmol) of -2-methyl-propionate at rt. The mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 1/1) to give the title compound as a pale red solid (0). .060 g, 74.0%).

MS (ESI, pose.ion) m / z: 672.2 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.72 (s, 1H), 7.56-7.49 (m, 1H), 7.35 (t, J = 7.0Hz 1H), 7.24 (d) , J = 6.2Hz 1H), 7.05 (t, J = 7.5Hz, 1H), 6.89 (d, J = 8.0Hz, 1H), 5.32-5.24 (m, 1H) ), 4.20-4.12 (m, 1H), 4.08-4.06 (m, 1H), 3.89 (s, 3H), 3.77-3.71 (m, 1H), 3.59-3.52 (m, 1H), 2.87 (s, 3H), 2.86 (s, 3H), 2.54-2.48 (m, 2H), 2.14-2. 01 (m, 4H), 1.88 (s, 3H), 1.88 (s, 3H), 1.85-1.65 (m, 4H).

工程１）２－（２－メトキシフェニル）－２－［（１Ｓ，２Ｒ，４Ｓ）－１，７，７－トリメチルノルボルン－２－イル］オキシ－酢酸
無水テトラヒドロフラン（４０ｍＬ）中の２－ノルネオール（３．９０ｇ、１２．２ｍｍｏｌ）の溶液に、水素化ナトリウム（１．９６ｇ、４９．０ｍｍｏｌ）をＮ_２下、一部ずつ氷浴上で添加した。１時間ｒｔで撹拌した後、無水テトラヒドロフラン（５０ｍＬ）中の２－ブロモ－２－（メトキシフェニル）酢酸（３．００ｇ、１２．２ｍｍｏｌ）の溶液を混合物に滴下した。滴下の後、混合物をｒｔに移し、更に８時間撹拌した。混合物を水（４０ｍＬ）を氷浴上で滴下することによってクエンチし、得られた混合物を濃縮して溶媒の大半を除去し、水相を酢酸エチル（４０ｍＬ×２）で洗浄した。併せた水層を希塩酸（４Ｎ）でｐＨ約３に調節し、次いで、酢酸エチル（４０ｍＬ×２）で抽出した。併せた有機層を飽和塩水（３０ｍＬ）で洗浄し、無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮して、標題化合物を淡黄色の油として得た（３．９０ｇ、１００％）。この粗生成物を更なる精製をすることなく次の工程に用いた。 Example 30: 2- [1- [2- (2-methoxyphenyl) -2 [(1S, 2S, 4S) -1,7,7-trimethylnorborn-2-yl] oxy-ethyl] -5-methyl -6-Oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid

Step 1) 2- (2-Methoxyphenyl) -2-[(1S, 2R, 4S) -1,7,7-trimethylnorborn-2-yl] oxy-acetic acid 2-norneol in anhydrous tetrahydrofuran (40 mL) Sodium hydride (1.96 g, 49.0 mmol) was added to the solution (3.90 g, 12.2 mmol) in portions under N ₂ on an ice bath. After stirring at rt for 1 hour, a solution of 2-bromo-2- (methoxyphenyl) acetic acid (3.00 g, 12.2 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise to the mixture. After the dropping, the mixture was transferred to rt and stirred for another 8 hours. The mixture was quenched by dropping water (40 mL) on an ice bath, the resulting mixture was concentrated to remove most of the solvent and the aqueous phase was washed with ethyl acetate (40 mL × 2). The combined aqueous layer was adjusted to pH about 3 with dilute hydrochloric acid (4N) and then extracted with ethyl acetate (40 mL × 2). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (3.90 g, 100%). This crude product was used in the next step without further purification.

MS (ESI, neg.ion) m / z: 317.3 [MH] ^- .

Step 2) 2- (2-Methoxyphenyl) -2-[(1S, 2R, 4S) -1,7,7-trimethylnorborn-2-yl] oxy-ethanol 2- (2-methoxyphenyl) -2 -[(1S, 2R, 4S) -1,7,7-trimethylnorborn-2-yl] oxy-acetic acid (3.90 g, 12.2 mmol) was dissolved in tetrahydrofuran (40 mL). The mixture was cooled to 0 ° C. under N ₂ and lithium aluminum hydride (0.93 g, 25.0 mmol) was added in portions. The mixture was stirred at rt overnight. The mixture was quenched by dropping water (30 mL) on an ice bath. The resulting mixture was adjusted to pH about 2 with hydrochloric acid (4N) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 6/1) to give the title compound as a colorless oil (0.100 g, 2.68%).

MS (ESI, pose.ion) m / z: 327.1 [M + Na] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.47-7.39 (m, 1H), 7.30-7.24 (m, 1H), 7.02-6.96 (m, 1H), 6. 90-6.85 (m, 1H), 4.97-4.89 (m, 1H), 3.84 (d, J = 1.1Hz, 3H), 3.77-3.69 (m, 1H) ) 3.68-3.61 (m, 1H) 3.60-3.48 (m, 1H) 2.33-2.29 (m, 1H) 2.20-2.10 (m) , 1H) 1.81-1.67 (m, 2H), 1.37-1.23 (m, 3H), 1.00 (s, 1H), 0.94-0.90 (m, 1H) ), 0.89-0.87 (m, 2H), 0.86 (d, J = 2.6Hz, 3H), 0.77 (d, J = 19.0Hz, 3H).

Step 3) 2- [1- [2- (2-Methoxyphenyl) -2 [(1S, 2S, 4S) -1,7,7-trimethylnorborn-2-yl] oxy-ethyl] -5-methyl -6-Oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl (diphenyl) silyl 2- (2-methoxyphenyl) ) -2-[(1S, 2R, 4S) -1,7,7-trimethylnorborn-2-yl] oxy-ethanol (0.14 g, 0.46 mmol), triphenylphosphine (0.25 mg, 0. 92 mmol) and 2-methyl-2- (5-methyl-6-oxazole-2-yl-2,4-dioxo-1H-thieno [2,3-d] pyrimido-3-yl) t-butyl propionate ( Diphenyl) Cyril (0.29 g, 0.51 mmol) was added to tetrahydrofuran (5 mL). Diisopropyl azodicarboxylate (0.19 mL, 0.95 mmol) was added dropwise to the mixture under _N2 . The mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 8/1) to give the title compound as a colorless oil (0.38 g, 96.3%).

Step 4) 2- [1- [2- (2-Methoxyphenyl) -2 [(1S, 2S, 4S) -1,7,7-trimethylnorborn-2-yl] oxy-ethyl] -5-methyl -6-Oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid 2- [1- [2- (2-methoxyphenyl)) -2 [(1S, 2S, 4S) -1,7,7-trimethylnorborn-2-yl] oxy-ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [ 2,3-d] Pyrimid-3-yl] -2-methyl-propionic acid t-butyl (diphenyl) silyl (0.38 g, 0.44 mmol) was dissolved in tetrahydrofuran (6 mL). A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mol / L, 0.70 mL, 0.67 mmol) was added to the mixture. The mixture was stirred at rt for 2 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a grayish white solid (0.90 mg, 31.5%).

MS (ESI, pose.ion) m / z: 622.4 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.72 (s, 1H), 7.59-7.54 (m, 1H), 7.34-7.29 (m, 1H), 7.24 (s, 1H), 7.04 (t, J = 7.5Hz, 1H), 6.90 (d, J = 8.2Hz, 1H), 5.31-5.26 (m, 1H), 4.23- 3.90 (m, 2H), 3.91 (s, 3H), 3.50 (d, J = 8.3Hz, 1H), 2.87 (s, 3H), 2.04-1.95 ( m, 1H), 1.92 (s, 3H), 1.87 (s, 3H), 1.83-1.74 (m, 1H), 1.66-1.57 (m, 1H), 1 .13-1.03 (m, 1H), 0.92-0.84 (m, 2H), 0.81 (s, 3H), 0.75 (s, 3H), 0.65 (s, 3H) ), 0.64-0.58 (m, 1H).

工程１）２－（１－アダマンチルメトキシ）－２－（２－メトキシフェニル）酢酸
１－アダマンタンメタノール（１．００ｇ、６．０１ｍｍｏｌ）をテトラヒドロフラン（２０ｍＬ）に溶解した。混合物をＮ_２下で０℃まで冷却し、水素化ナトリウム（７２２ｍｇ、１８．０５ｍｍｏｌ）を添加した。混合物を１０分間撹拌し、更にｒｔで３０分間撹拌し、次いで、２－ブロモ－２－（２－メトキシフェニル）酢酸（１．４０ｇ、５．７０ｍｍｏｌ）を添加した。得られた混合物をｒｔで２時間撹拌した。混合物を０℃まで冷却し、水（５０ｍＬ）でクエンチした。混合物を１０分間撹拌した。混合物を分配した後、水相を希塩酸（１Ｎ）でｐＨ約３に調節し、酢酸エチル（１００ｍＬ×３）で抽出した。併せた有機相を飽和含水ＮａＣｌで洗浄し、無水硫酸ナトリウム上で乾燥し、濾過した。濾液を真空濃縮して、標題化合物を赤色の油として得た（１．３０ｇ、６５．３％）。 Example 31: 2- [1- [2- (1-adamantylmethoxy) -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2] , 3-d] Pyrimid-3-yl] -2-methyl-propanoic acid

Step 1) 2- (1-adamantylmethoxy) -2- (2-methoxyphenyl) acetic acid 1-adamantane Methanol (1.00 g, 6.01 mmol) was dissolved in tetrahydrofuran (20 mL). The mixture was cooled to 0 ° C. under N ₂ and sodium hydride (722 mg, 18.05 mmol) was added. The mixture was stirred for 10 minutes and then at rt for 30 minutes, then 2-bromo-2- (2-methoxyphenyl) acetic acid (1.40 g, 5.70 mmol) was added. The resulting mixture was stirred at rt for 2 hours. The mixture was cooled to 0 ° C. and quenched with water (50 mL). The mixture was stirred for 10 minutes. After partitioning the mixture, the aqueous phase was adjusted to pH about 3 with dilute hydrochloric acid (1N) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a red oil (1.30 g, 65.3%).

MS (ESI, neg.ion) m / z: 329.1 [MH] ^- .

Step 2) 2- (1-adamantylmethoxy) -2- (2-methoxyphenyl) ethanol 2- (1-adamantylmethoxy) -2- (2-methoxyphenyl) acetic acid (500 mg, 1.51 mmol) in tetrahydrofuran (20 mL) ) Dissolved. The mixture was cooled to 0 ° C. under N ₂ and lithium aluminum hydride (118 mg, 3.02 mmol) was added in portions. The mixture was stirred at rt for 9 hours. Water (0.1 mL), aqueous sodium hydroxide solution (0.1 mL, 10%) and water (0.3 mL) were slowly added dropwise to the mixture in order to quench the reaction. The mixture was then stirred at rt for 15 minutes, anhydrous sodium sulfate was added and the resulting mixture was further stirred at rt for 30 minutes. The mixture was filtered. The filter cake was washed with EtOAc (10 mL x 4). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 7/3) to give the title compound as a pale yellow oil (60 mg, 12.5%).

MS (ESI, pose.ion) m / z: 339.1 [M + Na] ⁺ .

Step 3) 2- [1- [2- (1-adamantylmethoxy) -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2] , 3-d] Pyrimid-3-yl] -2-methyl-propionic acid t-butyl (diphenyl) Cyril 2- (1-adamantylmethoxy) -2- (2-methoxyphenyl) ethanol (169 mg, 0.53 mmol) , Diisopropyl azodicarboxylate (202 mg, 0.98 mmol) and 2-methyl-2- (5-methyl-6-oxazol-2-yl-2,4-dioxo-1H-thieno [2,3-d] pyrimido- 3-Il) t-butyl (diphenyl) silyl (280 mg, 0.49 mmol) propionate was added to tetrahydrofuran (10.0 mL). A solution of triphenylphosphine (295 mg, 0.98 mmol) in tetrahydrofuran (1.0 mL) was added dropwise to the mixture under _N2 . The mixture was stirred at rt for 22 hours and concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 15/1) to give the title compound as a grayish white oil (292 mg, 68.6%).

Step 4) 2- [1- [2- (1-adamantylmethoxy) -2- (2-methoxyphenyl) ethyl] -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2] , 3-d] Pyrimid-3-yl] -2-methyl-propanoic acid 2- [1- [2- (1-adamantylmethoxy) -2- (2-methoxyphenyl) ethyl] -5-methyl-6- Oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionate t-butyl (diphenyl) silyl (280 mg, 0.32 mmol) is prepared in tetrahydrofuran (0.32 mmol). It was dissolved in 10.0 mL). A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mmol / L, 2.0 mL, 2.00 mmol) was added to the mixture. The mixture was stirred at rt for 5 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a grayish white solid (78 mg, 38.3%).

MS (ESI, pose.ion) m / z: 634.2 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.68 (d, J = 8.1 Hz, 1H), 7.46-7.44 (m, 1H), 7.31-7.27 (m, 1H), 7.22 (s, 1H), 7.03-6.99 (m, 1H), 6.90-6.85 (m, 1H), 5.19-5.15 (m, 1H), 4. 20-1.16 (m, 1H), 4.07-3.95 (m, 1H), 3.85 (s, 3H), 3.06-3.00 (m, 1H), 2.83 ( s, 3H) 2.66 (d, J = 9.0Hz, 1H) 1.90-1.87 (m, 3H) 1.86-1.80 (m, 6H), 1.63- 1.56 (m, 4H), 1.52-1.47 (m, 2H), 1.43-1.38 (m, 3H), 1.36-1.30 (m, 3H).

工程１）［（１Ｒ，２Ｓ，３Ｓ，４Ｒ，５Ｒ）－３－ヒドロキシ－４－（ｐ－トリルスルホニル）－６，８－ジオキサビシクロ［３．２．１］オクタ－２－イル］－４－メチルベンゼンスルホン酸
ピリミジン（１８ｍＬ）中の（１Ｒ，２Ｓ，３Ｓ，４Ｒ，５Ｒ）－６，８－ジオキサビシクロ［３．２．１］オクタン－２，３，４－トリオール（３．００ｇ、１８．５ｍｍｏｌ）の溶液に、ｐ－トルエンスルホニルクロリド（７．８４ｇ、４０．７ｍｍｏｌ）を－１０℃でＮ_２下で添加した。混合物を－１０℃で一晩撹拌した。混合物を水（３００ｍＬ）でクエンチし、２０分間撹拌し、濃縮して水を取り除いた。残分をＥｔＯＡｃ（１５０ｍＬ）に溶解した。混合物を飽和塩化アンモニウム溶液（１００ｍＬ）及び飽和塩水（１００ｍＬ）で洗浄し、無水硫酸ナトリウム上で乾燥し、濾過した。濾液を真空濃縮した。残分をシリカゲルクロマグラフィー（ＰＥ／ＥｔＯＡｃ（Ｖ／Ｖ）＝２／１）で精製して、標題化合物を灰白色の固体として得た（７．３１ｇ、８４．０％）。 Example 32: 2- [1- [2-[[(1S, 3S, 5R) -6,8-dioxabicyclo [3.2.1] octa-3-yl] oxy] -2- (2-methoxy) Phenyl) -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid

Step 1) [(1R, 2S, 3S, 4R, 5R) -3-hydroxy-4- (p-tolylsulfonyl) -6,8-dioxabicyclo [3.2.1] octa-2-yl]- (1R, 2S, 3S, 4R, 5R) -6,8-dioxabicyclo [3.2.1] octane-2,3,4-triol (3.) in pyrimidin (18 mL) 4-methylbenzenesulfonic acid. To a solution of 00 g, 18.5 mmol) was added p-toluenesulfonyl chloride (7.84 g, 40.7 mmol) at −10 ° C. under _N2 . The mixture was stirred at −10 ° C. overnight. The mixture was quenched with water (300 mL), stirred for 20 minutes and concentrated to remove water. The residue was dissolved in EtOAc (150 mL). The mixture was washed with saturated ammonium chloride solution (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 2/1) to give the title compound as a grayish white solid (7.31 g, 84.0%).

MS (ESI, pose.ion) m / z: 471.2 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, DMSO) δ7.79 (dd, J = 8.2, 4.8 Hz, 4H), 7.49 (dd, J = 8.2, 3.0 Hz, 5H), 6.05 ( d, J = 4.2Hz, 1H) 5.27 (s, 1H), 4.54 (d, J = 5.3Hz, 1H), 4.32 (s, 1H), 4.04 (s, 1H), 4.02 (d, J = 4.9Hz, 1H), 3.59-3.52 (m, 2H), 2.46 (d, J = 4.7Hz, 1H), 2.43 ( s, 6H).

Step 2) [(1R, 2S, 3S, 4R, 5R)-in (1S, 3S, 5R) -6,8-dioxabicyclo [3.2.1] octane-3-ol anhydrous tetrahydrofuran (50 mL)- 3-Hydroxy-4- (p-tolylsulfonyl) -6,8-dioxabicyclo [3.2.1] octa-2-yl] -4-methylbenzenesulfonic acid (6.74 g, 14.32 mmol) Lithium aluminum hydride (5.60 g, 143 mmol) was added to the solution in portions. After the system was stable, the mixture was stirred at 70 ° C. overnight. The mixture was quenched at −10 ° C. with water (2 mL), EtOAc (50 mL) and anhydrous sodium sulfate (10 g) were added, the mixture was stirred for 10 minutes and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a white solid (0.364 g, 19.5%).

GC-MS: 130.00;
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ5.42 (s, 1H), 4.44 (s, 1H), 4.22 (d, J = 6.2 Hz, 1H), 3.89 (t, J = 5.1Hz, 1H), 3.54-3.48 (m, 1H), 3.40 (s, 1H), 2.04-1.98 (m, 1H), 1.81-1. 75 (m, 1H), 1.73-1.64 (m, 2H).

Step 3) 2-[[(1S, 3S, 5R) -6,8-dioxabicyclo [3.2.1] octa-3-yl] oxy] -2- (2-methoxyphenyl) acetic acid (1S, 3S, 5R) -6,8-dioxabicyclo [3.2.1] octane-3-ol (0.364 g, 2.80 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). The mixture was cooled to 0 ° C. under N ₂ and sodium hydride (0.29 g, 7.3 mmol, 60%) was added. The mixture is stirred for 10 minutes, then stirred in rt for 1 hour, then a solution of 2-bromo-2- (2-fluorophenyl) acetic acid (0.600 g, 2.45 mmol) in anhydrous tetrahydrofuran (4 mL) is added. did. The resulting mixture was stirred at rt overnight. The mixture was poured into ice water (50 g) to quench the reaction, then ethyl acetate (10 mL) was added. The mixture was stirred for 10 minutes. After partitioning the mixture, the aqueous phase was adjusted to pH about 2 with dilute hydrochloric acid (1N) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a pale tan oil (0.721 g, 100%).

Step 4) 2-[[(1S, 3S, 5R) -6,8-dioxabicyclo [3.2.1] octa-3-yl] oxy] -2- (2-methoxyphenyl) ethanol 2-[ [(1S, 3S, 5R) -6,8-dioxabicyclo [3.2.1] octa-3-yl] oxy] -2- (2-methoxyphenyl) acetic acid (0.721 g, 2.45 mmol) Was dissolved in anhydrous tetrahydrofuran (15 mL). The mixture was cooled to 0 ° C. under N ₂ and lithium aluminum hydride (0.19 g, 5.0 mmol) was added in portions. The mixture was stirred for 4.5 hours. The mixture was quenched with water (2 mL) at 0 ° C. Then EtOAc (50 mL) and anhydrous sodium sulfate (5 g) were added and the resulting mixture was stirred for 10 minutes. The mixture was filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromagraphy (PE / EtOAc (V / V) = 1/1) to give the title compound (0.435 g, 63.3%).

MS (ESI, pose.ion) m / z: 303.2 [M + Na] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.42 (dd, J = 7.5, 1.1 Hz, 1H), 7.30-7.24 (m, 1H), 6.98 (t, J = 7) .4Hz, 1H), 6.86 (d, J = 8.2Hz, 1H), 5.66 (s, 1H), 4.93 (dd, J = 9.4, 2.5Hz, 1H), 4 .59 (s, 1H), 4.53 (d, J = 6.5Hz, 1H), 3.90-3.85 (m, 1H), 3.83 (s, 3H), 3.79 (t) , J = 5.3Hz, 1H), 3.73 (d, J = 10.2Hz, 1H), 3.67 (s, 1H), 3.43 (dd, J = 10.9, 9.6Hz, 1H), 2.38 (d, J = 15.0Hz, 1H), 2.27-2.21 (m, 1H), 2.01 (d, J = 14.6Hz, 1H), 1.76- 1.69 (m, 1H).

Step 5) 2- [1- [2-[[(1S, 3S, 5R) -6,8-dioxabicyclo [3.2.1] octa-3-yl] oxy] -2- (2-methoxy) Phenyl) -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl (diphenyl) silyl 2 -[[(1S, 3S, 5R) -6,8-dioxabicyclo [3.2.1] octa-3-yl] oxy] -2- (2-methoxyphenyl) ethanol (81 mg, 0.29 mmol) , Diisopropyl azodicarboxylate (0.08 mL, 0.40 mmol) and 2-methyl-2- (5-methyl-6-oxazol-2-yl-2,4-dioxo-1H-thieno [2,3-d]] T-butyl (diphenyl) silyl (150 mg, 0.261 mmol) of pyrimido-3-yl) -propionate was dissolved in tetrahydrofuran (10 mL). Triphenylphosphine (105 mg, 0.392 mmol) was added to the mixture in portions under _N2 . The mixture was stirred at rt for 10 hours. The reaction mixture was concentrated in vacuo to remove solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 3/1) to give the title compound as a grayish white solid (219 mg, 100%).

Step 6) 2- [1- [2-[[(1S, 3S, 5R) -6,8-dioxabicyclo [3.2.1] octa-3-yl] oxy] -2- (2-methoxy) Phenyl) -5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid 2- [1- [2- [2-] [[(1S, 3S, 5R) -6,8-dioxabicyclo [3.2.1] octa-3-yl] oxy] -2- (2-methoxyphenyl) -5-methyl-6-oxazole- 2-Il-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionic acid t-butyl (diphenyl) silyl (219 mg, 0.262 mmol) in tetrahydrofuran (4 mL) Dissolved in. A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mol / L, 0.52 mL, 0.52 mmol) was added to the mixture. The mixture was stirred at rt for 2 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with (DCM / MeOH (V / V) = 8/1) to give the title compound as a white solid, 81 mg, 52%).

MS (ESI, pose.ion) m / z: 598.3 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.73 (s, 1H), 7.50 (dd, J = 7.5, 1.1 Hz, 1H), 7.35-7.30 (m, 1H), 7.24 (s, 1H), 7.04 (t, J = 7.4Hz, 1H), 6.91 (d, J = 8.2Hz, 1H), 5.48 (dd, J = 9.7) 4.3Hz, 1H), 5.40 (s, 1H), 4.38-4.30 (m, 1H), 4.29-4-23 (m, 1H), 3.91 (s, 3H) ), 3.75-3.65 (m, 1H), 3.51-3.45 (m,), 3.44-3.38 (m, 1H), 2.89 (s, 3H), 2 .12-2.05 (m, 1H), 2.05-1.94 (m, 1H), 1.92 (s, 3H), 1.91 (s, 3H), 1.88-1.76 (M, 2H), 1.62-1.57 (m, 1H).

２－［１－［２－［［（２Ｓ，３ａＲ，６ａＳ）－１，２，３，３ａ，４，６ａ－ヘキサヒドロペンタレン－２－イル］オキシ］－２－（２－メトキシフェニル）エチル）－５－メチル－６－オキサゾール－２－イル－２，４－ジオキソ－チエノ［２，３－ｄ］ピリミド－３－イル］－２－メチル－プロピオン酸ｔ－ブチル（ジフェニル）シリル（２３０ｍｇ、０．２７ｍｍｏｌ）をテトラヒドロフラン（１０．０ｍＬ）に溶解した。混合物にテトラヒドロフラン中のフッ化テトラブチルアンモニウムの溶液（１．０ｍｏｌ／Ｌ、２．３ｍＬ、２．３ｍｍｏｌ）を添加した。混合物をｒｔで２時間撹拌した。混合物に水（１０ｍＬ）及び酢酸エチル（２０ｍＬ×２）を添加した。得られた混合物を分配した。有機層を飽和塩水で洗浄し、無水硫酸ナトリウム上で乾燥し、吸引濾過により濾過した。濾液を真空濃縮した。残分をｐｒｅ－ＨＰＬＣで精製して、標題化合物を白色の固体として得た（４９ｍｇ、２９．０％）。 Example 33: 2- [1- [2-[[(2S, 3aR, 6aS) -1,2,3,3a, 4,6a-hexahydropentalene-2-yl] oxy] -2- (2-) Methoxyphenyl) ethyl) -5-methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propanoic acid

2- [1- [2-[[(2S, 3aR, 6aS) -1,2,3,3a, 4,6a-hexahydropentalene-2-yl] oxy] -2- (2-methoxyphenyl) Ethyl) -5-Methyl-6-oxazole-2-yl-2,4-dioxo-thieno [2,3-d] pyrimido-3-yl] -2-methyl-propionate t-butyl (diphenyl) silyl ( 230 mg, 0.27 mmol) was dissolved in tetrahydrofuran (10.0 mL). A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mol / L, 2.3 mL, 2.3 mmol) was added to the mixture. The mixture was stirred at rt for 2 hours. Water (10 mL) and ethyl acetate (20 mL x 2) were added to the mixture. The resulting mixture was dispensed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered by suction filtration. The filtrate was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound as a white solid (49 mg, 29.0%).

MS (ES / API, pose.ion) m / z: 592.2 [M + H] ⁺ ;
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.28-7.24 (m, 2H), 7.22 ( s, 1H), 7.03-6.99 (m, 1H), 6.83 (d, J = 8.2Hz, 1H), 5.58-5.33 (m, 2H), 5.32- 5.25 (m, 1H), 4.13-3.96 (m, 2H), 3.83 (s, 3H), 3.73-3.66 (m, 1H), 2.95-2. 86 (m, 1H), 2.84 (s, 3H), 2.50-2.36 (m, 2H), 2.06-1.90 (m, 3H), 1.86 (s, 3H) 1.83 (s, 3H), 1.35-1.26 (m, 2H).

Biological assay 1. Acetyl-CoA carboxylase inhibitory activity assay in vitro 1) Test method The inhibitory effect of the compound on ACC1 or ACC2 was determined using the ADP-Clo® kinase assay kit manufactured by Promega. The ADP-Glo® kinase assay is a luminescent ADP detection assay that measures enzyme activity by quantifying purified ADP during an enzymatic reaction. The assay is performed in two steps, first after the enzymatic reaction, the same amount of ADP-Glo® reagent is added to terminate the reaction and deplete the remaining ATP. Second, a kinase detection reagent is added, ADP is converted to ATP at the same time, and the newly synthesized ATP is measured using a luciferase / luciferin reaction. Emission can be correlated with the concentration of ADP by using the ATP vs. ADP conversion curve.

The detailed procedure is as follows.
a. 4.5 μL / well of ACC1 / ACC2 working solution (2.22 nM) was added to a 384-well reaction plate (PerkinElmer, 6007290).
b. Compound (10 mM) was diluted 500-fold with 100% DMSO to 20 μM, and the diluted compound solution was subsequently diluted 1: 3 on a 384-well dilution plate (3657, Corning) to 20, 6.67, 2. The concentration gradients were 22, 0.74, 0.25, 0.082, 0.027, 0.009, 0.003, 0.001, and 0 μM.
c. A 0.5 μL / well compound solution (prepared in step b) was added to the 384-well reaction plate (prepared in step a), the plate was centrifuged at 1000 rpm and incubated at 25 ° C. for 15 minutes.
d. A 0.5 μL / well substrate mixture (ATP (10 mM), acetyl CoA (2 mM), NaHCO ₃ (1000 mM)) was transferred to a 384-well reaction plate, the plate was centrifuged at 1000 rpm and incubated at 25 ° C. for 30 minutes. The final concentration gradient of the compound in the reaction system is 1000, 333.3, 111.1, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, 0 nM. there were. The final concentration of DMSO was 5% and the final concentration of ACC1 / ACC2 was 1 nM.
e. A 10 μL / well ADP-Glo solution was transferred to a 384-well reaction plate, the plate was centrifuged at 1000 rpm and incubated at 25 ° C. for 40 minutes.
f. A 20 μL / well kinase detection reagent was transferred to a 384-well reaction plate, the plate was centrifuged at 1000 rpm and incubated at 25 ° C. for 40 minutes.
g. Relative emission amount (RLU) was read on an Envision multifunction plate reader. The signal intensity represents the level of ACC1 / ACC2 kinase activity.

The ACC1 / ACC2 working solution, substrate mixture, ADP-Glo solution and kinase detection reagent used in the assay were all 1 × kinase reaction buffer [hydroxyethylpiperazine ethanesulfonic acid (HEPES, 50 mM), MgCl2 (2 mM), laurylpoly. Glycol ether (BRIJ-35, 0.01%), potassium citrate (2 mM), bovine serum albumin (BSA, 50 μg / mL), dithioreagent (DDT, 2 mM)] was used.

The standard deviation was calculated by averaging the data for each concentration as well as the positive and negative controls. The inhibition rate was calculated by the formula: 100 × (mean negative control-compound) / (mean negative control-mean positive control). Non-linear regression equation for IC ₅₀ of each compound: Y = Bottom + (Top-Bottom) / (l + 10 ^ ((LogIC ₅₀ -X) xHillSlope)), (where X is the log of the compound concentration and Y is the inhibition rate. It was calculated by matching the data with). 0.1 μM ND-630 was used as the positive control in the assay.

アッセイの結果は、本発明の化合物がＡＣＣ１及び／又はＡＣＣ２に良好な阻害活性を有することを示している。 2. 2. Results Table 2 shows the results of the ACC1 and ACC2 inhibition assays for the compounds of the present invention in vitro.

The results of the assay show that the compounds of the invention have good inhibitory activity on ACC1 and / or ACC2.

2. 2. Pharmacokinetic test 1) Test method Experimental animals: 6 healthy male SD rats (purchased from Hunan SJA Laboratory Animal Co .; Ltd) were randomly divided into 2 groups and 3 animals in each group. It was administered by intravenous injection or forced feeding.

Preparation of Drugs: Compounds were surveyed and target concentrations of compounds were prepared by addition of 5% DMSO, 10% Kolliphor HS15 and 85% saline (0.9%).

Administration and sampling: Animals were fasted for 12 hours before administration and 3 hours after administration, and SD rats were injected intravenously (1 mg / kg) and gavage (PO, 5 mg / kg) from the leg veins of the hind limbs. Was just administered by.

200-400 μL of blood was taken from the rat tail vein at different time points 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h. Blood collected at each time point was placed in a K2EDTA anticoagulant tube and stored in a couveuse with an ice sac. After 15 minutes, all samples were centrifuged at 4600 r / min at 4 ° C. for 5 minutes to obtain plasma samples, the concentration of compounds in the plasma samples was measured by LC / MS / MS, and the pharmacokinetic parameters were changed to the drug. Calculated based on concentration-time curve.

The pharmacokinetic properties of the compounds of the invention were tested by the above example.

2) Test results The plasma concentration and exposure level of the compound of the present invention in rats increased after oral administration of the compound of the present invention, the clear rate was low, and the bioavailability was good. The compounds of the present invention had good pharmacokinetic characteristics.

（式中、
Ｈｅｔは、－Ｃ（＝Ｏ）ＮＲ ^ａ Ｒ ^ｂ 、－Ｃ（＝ＮＲ）ＮＲ ^ａ Ｒ ^ｂ 、－ＮＨ－Ｃ（＝ＮＲ）ＮＲ ^ａ Ｒ ^ｂ 、３～１０員のヘテロシクリル又は５～１０員のヘテロアリールであり、ここで、３～１０員のヘテロシクリル及び５～１０員のヘテロアリールの各々は、独立に及び任意に、Ｈ、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ _１－６ アルキル、Ｃ _１－６ アルコキシ、Ｃ _１－６ ハロアルキル、カルボキシ及び－Ｃ（＝Ｏ）ＮＨ _２ で置換されていてもよく、
Ｒ ^１ は、Ｈ、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ _１－６ アルキル、Ｃ _１－６ アルコキシ又はＣ _１－６ ハロアルキルであり、
Ｒ ^２ は、－ＯＲ又は－ＮＲ ^ａ Ｒ ^ｂ であり、
Ｒ ^３ 及びＲ ^４ の各々は、独立に、Ｈ、Ｄ、Ｃ _１－６ アルキル、Ｃ _１－６ ヒドロキシアルキル又はＣ _１－６ ハロアルキルであり、
Ｌは、－Ｏ－、－Ｏ－メチレン－、－Ｏ－エチレン－、－Ｓ－又は－ＮＨ－であり、
Ｒ ^５ は、Ｃ _６－１０ アリール又は５～１０員のヘテロアリールであり、ここで、Ｃ _６－１０ アリール及び５～１０員のヘテロアリールの各々は、独立に及び任意に、１個、２個又は３個のＲ ^６ で置換されていてもよく、ここで、Ｒ ^６ は、Ｈ、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ _１－６ アルキル、Ｃ _１－６ アルコキシ、Ｃ _１－６ ハロアルキル、Ｃ _１－６ ハロアルコキシ、Ｃ _１－６ シアノアルキル又はＣ _１－６ ヒドロキシアルキルであり、
Ｗは、縮合シクリル、架橋シクリル又はスピロシクリルであり、ここで、縮合シクリル、架橋シクリル又はスピロシクリルは、Ｎ、Ｏ又はＳから独立に選択される、０個、１個、２個、３個又は４個のヘテロ原子を含む飽和又は部分的に不飽和の６～１２員のシクリルであり、ここで、Ｗは、任意に、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、－Ｃ（＝Ｏ）ＯＲ、－Ｃ（＝Ｏ）ＮＲ ^ａ Ｒ ^ｂ 、－Ｃ（＝ＮＲ）ＮＲ ^ａ Ｒ ^ｂ 、－ＮＨ－Ｃ（＝ＮＲ）ＮＲ ^ａ Ｒ ^ｂ 、－ＳＯ _２ Ｒ、－ＳＯ _２ ＮＲ ^ａ Ｒ ^ｂ 、Ｃ _１－６ アルキル、Ｃ _３－６ シクロアルキル、Ｃ _１－６ アルコキシ、Ｃ _１－６ ハロアルコキシ、Ｃ _１－６ アルキルアミノ、Ｃ _１－６ ハロアルキル、Ｃ _１－６ シアノアルキル及びＣ _１－６ ヒドロキシアルキルから独立に選択される１個、２個、３個、４個又は５個の置換基で置換されていてもよく、
ここで、Ｒ、Ｒ ^ａ 及びＲ ^ｂ の各々は、独立に、Ｈ、Ｄ、Ｃ _１－６ アルキル、Ｃ _１－６ ハロアルキル又はＣ _３－８ シクロアルキルであるか、又はＲ ^ａ 及びＲ ^ｂ は、それらが結合しているＮ原子と一緒に、３～１０員のヘテロシクリルを形成し、ここで、３～１０員のヘテロシクリルは、任意に、オキソ（＝Ｏ）、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ _１－６ アルキル、Ｃ _１－６ アルコキシ及びＣ _１－６ ハロアルキルで置換されていてもよい）を有する化合物又はその立体異性体、幾何異性体、互変異性体、Ｎ－オキシド、水和物、溶媒和物、代謝産物、薬学的に許容され得る塩若しくはプロドラッグ。
［２］ Ｈｅｔは、５～６員のヘテロシクリル又は５～６員のヘテロアリールであり、ここで、５～６員のヘテロシクリル及び５～６員のヘテロアリールの各々は、独立に及び任意に、Ｈ、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ _１－３ アルキル、Ｃ _１－３ アルコキシ、Ｃ _１－３ ハロアルキル、カルボキシ及び－Ｃ（＝Ｏ）ＮＨ _２ で置換されていてもよい、付記［１］に記載の化合物。
［３］ Ｈｅｔは、ピロリジル、テトラヒドロフリル、イミダゾリジニル、ピラゾリジル、テトラヒドロピラニル、ピペリジル、ピペラジニル、モルホリニル、チオモルホリニル、ピロリル、フリル、チエニル、ピラゾリル、イミダゾリル、オキサゾリル、チアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジニル、ピリダジニル又はピラジニルであり、ここで、ピロリジル、テトラヒドロフリル、イミダゾリジニル、ピラゾリジル、テトラヒドロピラニル、ピペリジル、ピペラジニル、モルホリニル、チオモルホリニル、ピロリル、フリル、チエニル、ピラゾリル、イミダゾリル、オキサゾリル、チアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジニル、ピリダジニル及びピラジニルの各々は、独立に及び任意に、Ｈ、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、メチル、エチル、イソプロピル、メトキシ、エトキシ、イソプロポキシ、トリフルオロメチル、ジフルオロメチル、カルボキシ及び－Ｃ（＝Ｏ）ＮＨ _２ で置換されていてもよい、付記［１］～［２］の何れか１項に記載の化合物。
［４］ Ｒ ^１ は、Ｈ、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ _１－３ アルキル、Ｃ _１－３ アルコキシ又はＣ _１－３ ハロアルキルであり、
Ｒ ^２ は、－ＯＲ又は－ＮＲ ^ａ Ｒ ^ｂ であり、
ここで、Ｒ、Ｒ ^ａ 及びＲ ^ｂ の各々は、独立に、Ｈ、Ｄ、Ｃ _１－３ アルキル、Ｃ _１－３ ハロアルキル又はＣ _３－６ シクロアルキルであるか、又はＲ ^ａ 及びＲ ^ｂ は、それらが結合しているＮ原子と一緒に、４～６員のヘテロシクリルを形成し、ここで、４～６員のヘテロシクリルは、任意に、オキソ（＝Ｏ）、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ _１－３ アルキル、Ｃ _１－３ アルコキシ及びＣ _１－３ ハロアルキルで置換されていてもよく、
Ｒ ^３ 及びＲ ^４ の各々は、独立に、Ｈ、Ｄ、Ｃ _１－３ アルキル、Ｃ _１－３ ヒドロキシアルキル又はＣ _１－３ ハロアルキルである、付記［１］～［３］の何れか１項に記載の化合物。
［５］ Ｒ ^１ は、Ｈ、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、メチル、エチル、メトキシ、エトキシ、イソプロポキシ、トリフルオロメチル、ジフルオロメチル又はトリフルオロエチルであり、
Ｒ ^２ は、－ＯＲ又は－ＮＲ ^ａ Ｒ ^ｂ であり、
ここで、Ｒ、Ｒ ^ａ 及びＲ ^ｂ の各々は、独立に、Ｈ、Ｄ、メチル、エチル、ｎ－プロピル、イソプロピル、トリフルオロメチル、ジフルオロメチル、トリフルオロエチル、シクロプロピル、シクロブチル、シクロペンチル又はシクロヘキシルであるか、又はＲ ^ａ 及びＲ ^ｂ は、それらが結合しているＮ原子と一緒に、式（ｉ－ａ）から（ｉ－ｋ）：

によって表されるヘテロシクリル基から選択されるヘテロシクリルを形成し、
ここで、式（ｉ－ａ）から（ｉ－ｋ）によって表されるヘテロシクリル基は、任意に、オキソ（＝Ｏ）、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、メチル、エチル、イソプロピル、メトキシ、エトキシ、トリフルオロメチル、ジフルオロメチル又はトリフルオロエチルで置換されていてもよく、
Ｒ ^３ 及びＲ ^４ の各々は、独立に、Ｈ、Ｄ、メチル、エチル、ｎ－プロピル、ヒドロキシメチル、ヒドロキシエチル、トリフルオロメチル又は２－フルオロエチルである、付記［１］～［４］の何れか１項に記載の化合物。
［６］ Ｒ ^５ は、フェニル、ナフチル、１，２，３，４－テトラヒドロナフチル又は５～６員のヘテロアリールであり、ここで、フェニル、ナフチル、１，２，３，４－テトラヒドロナフチル及び５～６員のヘテロアリールの各々は、独立に及び任意に、１個、２個又は３個のＲ ^６ で置換されていてもよく、ここで、Ｒ ^６ は、Ｈ、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、Ｃ _１－３ アルキル、Ｃ _１－３ アルコキシ、Ｃ _１－３ ハロアルキル、Ｃ _１－３ ハロアルコキシ、Ｃ _１－３ シアノアルキル又はＣ _１－３ ヒドロキシアルキルである、付記［１］～［５］の何れか１項に記載の化合物。
［７］ Ｒ ^５ は、フェニル、ナフチル、１，２，３，４－テトラヒドロナフチル、イミダゾリル、ピラゾリル、フリル、チエニル、オキサゾリル、オキサジアゾリル、チアゾリル、チアジアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジニル、ピラニル又はピリダジニルであり、ここで、フェニル、ナフチル、１，２，３，４－テトラヒドロナフチル、イミダゾリル、ピラゾリル、フリル、チエニル、オキサゾリル、オキサジアゾリル、チアゾリル、チアジアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジニル、ピラニル及びピリダジニルの各々は、独立に及び任意に、１個、２個又は３個のＲ ^６ で置換されていてもよく、ここで、Ｒ ^６ は、Ｈ、Ｄ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、メチル、エチル、ｎ－プロピル、イソプロピル、メトキシ、エトキシ、イソプロポキシ、トリフルオロメチル、ジフルオロメチル、トリフルオロメトキシ、ジフルオロメトキシ、ヒドロキシメチル、ヒドロキシエチル、シアノメチル又はシアノエチルである、付記［１］～［６］の何れか１項に記載の化合物。
［８］ Ｗは、次の構造：

のうち１つを有し、
Ｘ ^１ 、Ｘ ^２ 及びＸ ^３ の各々は、独立に、結合、－ＣＨ _２ －、－Ｏ－、－Ｓ－又は－ＮＨ
－であり、
Ｙは、ＣＨ又はＮであり、
ｒ、ｓ、ｔ及びｎの各々は、独立に、０、１、２又は３であり、
各Ｗは、任意に、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、－Ｃ（＝Ｏ）ＯＨ、－Ｃ（＝Ｏ）ＮＨ _２ 、－Ｃ（＝ＮＨ）ＮＨ _２ 、－ＮＨ－Ｃ（＝ＮＨ）ＮＨ _２ 、－ＳＯ _２ ＣＨ _３ 、－ＳＯ _２ Ｃ _２ Ｈ _５ 、Ｃ _１－３ アルキル、Ｃ _３－６ シクロアルキル、Ｃ _１－３ アルコキシ、Ｃ _１－３ ハロアルコキシ、Ｃ _１－３ アルキルアミノ、Ｃ _１－３ ハロアルキル、Ｃ _１－３ シアノアルキル及びＣ _１－３ ヒドロキシアルキルから独立に選択される１個、２個、３個、４個又は５個の置換基で置換されていてもよい、付記［１］～［７］の何れか１項に記載の化合物。
［９］ Ｗは、次の構造：

のうち１つを有し、
各Ｗは、任意に、Ｄ、オキソ（＝Ｏ）、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ヒドロキシ、アミノ、ニトロ、シアノ、－Ｃ（＝Ｏ）ＯＨ、－Ｃ（＝Ｏ）ＮＨ _２ 、－Ｃ（＝ＮＨ）ＮＨ _２ 、－ＮＨ－Ｃ（＝ＮＨ）ＮＨ _２ 、－ＳＯ _２ ＣＨ _３ 、－ＳＯ _２ Ｃ _２ Ｈ _５ 、メチル、エチル、イソプロピル、ｎ－ブチル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、トリフルオロメチル、ジフルオロメチル、メトキシ、エトキシ、イソプロポキシ、トリフルオロメトキシ、ジフルオロメトキシ、メチルアミノ、シアノメチル及びヒドロキシメチルから独立に選択される１個、２個、３個、４個又は５個の置換基で置換されていてもよい、付記［１］～［８］の何れか１項に記載の化合物。
［１０］ 次の構造：

のうち１つを有する付記［１］～［９］の何れか１項に記載の化合物又はその立体異性体、幾何異性体、互変異性体、Ｎ－オキシド、水和物、溶媒和物、代謝産物、薬学的に許容され得る塩若しくはプロドラッグ。
［１１］ 請求項１～１０の何れか１項に記載の化合物を含む医薬組成物。
［１２］ 薬学的に許容され得る担体、賦形剤、希釈剤、アジュバント、ビヒクル又はその組み合わせを更に含む、請求項１１に記載の医薬組成物。
［１３］ アセチルＣｏＡカルボキシラーゼによって制御される障害又は疾患を予防し、処置し、治療し、又は軽減するための医薬の製造における、付記［１］～［１０］の何れか１項に記載の化合物又は付記［１１］または［１２］に記載の医薬組成物の使用。
［１４］ 前記アセチルＣｏＡカルボキシラーゼによって制御される障害又は疾患は、代謝障害又は新生物障害である付記［１３］に記載の使用。
［１５］ 前記アセチルＣｏＡカルボキシラーゼによって制御される障害又は疾患は、インスリン抵抗性、肥満、脂質異常症、メタボリックシンドローム、ＩＩ型糖尿病、非アルコール性脂肪性肝疾患及び非アルコール性脂肪性肝炎を含む、付記［１３］に記載の使用。
［１６］ 前記新生物障害は、乳がん、膵がん、腎細胞がん、肝細胞がん、悪性黒色腫及び他の皮膚腫瘍、非小細胞性気管支がん、子宮内膜がん、結腸直腸がん並びに前立腺がんを含む、付記［１４］に記載の使用。
［１７］ 前記アセチルＣｏＡカルボキシラーゼによって制御される障害又は疾患を予防し、処置し、治療し、又は軽減することにおける使用のための、付記［１］～［１０］の何れか１項に記載の化合物又はに記載の医薬組成物。
［１８］ 前記アセチルＣｏＡカルボキシラーゼによって制御される障害又は疾患は、代謝障害又は新生物障害である、付記［１７］に記載の化合物又は医薬組成物。
［１９］ 前記アセチルＣｏＡカルボキシラーゼによって制御される障害又は疾患は、インスリン抵抗性、肥満、脂質異常症、メタボリックシンドローム、ＩＩ型糖尿病、非アルコール性脂肪性肝疾患及び非アルコール性脂肪性肝炎を含む、付記［１７］に記載の化合物又は医薬組成物。
［２０］ 前記新生物障害は、乳がん、膵がん、腎細胞がん、肝細胞がん、悪性黒色腫及び他の皮膚腫瘍、非小細胞性気管支がん、子宮内膜がん、結腸直腸がん並びに前立腺がんを含む、付記［１８］に記載の化合物又は医薬組成物。
［２１］ 付記［１］～［１０］の何れか１項に記載の化合物又は付記［１１］または［１２］に記載の医薬組成物の治療有効量を罹患体に投与することを含む、罹患体におけるアセチルＣｏＡカルボキシラーゼによって制御される障害又は疾患を予防し、処置し、治療し、又は軽減する方法。
［２２］ 前記アセチルＣｏＡカルボキシラーゼによって制御される障害又は疾患は、代謝障害又は新生物障害である、付記［２１］に記載の方法。
［２３］ 前記アセチルＣｏＡカルボキシラーゼによって制御される障害又は疾患は、インスリン抵抗性、肥満、脂質異常症、メタボリックシンドローム、ＩＩ型糖尿病、非アルコール性脂肪性肝疾患及び非アルコール性脂肪性肝炎を含む、付記［２１］に記載の方法。
［２４］ 前記新生物障害は、乳がん、膵がん、腎細胞がん、肝細胞がん、悪性黒色腫及び他の皮膚腫瘍、非小細胞性気管支がん、子宮内膜がん、結腸直腸がん並びに前立腺がんを含む、付記［２２］に記載の方法。 Finally, it should be noted that there are other ways to carry out the invention. Accordingly, embodiments of the invention may be described as examples, but the invention is not limited to what is described, and further modifications may be made within the scope of the invention, or equivalents may be claimed. Is added to the range of. All publications and patent documents cited herein are incorporated herein by reference.
<Additional Notes>
The inventions described in the original claims of the present application are described below.
[1] Equation (I)

(During the ceremony,
Het is -C (= O) NR ^a R ^b , -C (= NR) NR ^a R ^b , -NH-C (= NR) NR ^a R ^b , 3 to 10-membered heterocyclyl or 5 to 10-membered heterocyclyl. Heteroaryl, where each of the 3-10 membered heterocyclyl and the 5-10 membered heteroaryl independently and optionally H, D, oxo (= O), F, Cl, Br, I, It may be substituted with hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, carboxy and —C (= O) NH ₂ .
R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl.
R ² is -OR or -NR ^a R ^b , and is
Each of R ³ and R ⁴ is independently H, D, C _1-6 alkyl, C _1-6 hydroxyalkyl or C _1-6 haloalkyl.
L is -O-, -O-methylene-, -O-ethylene-, -S- or -NH-, and
R5 is a C _6-10 aryl or a 5-10 membered heteroaryl, where each of the C ^6-10 _aryl and the 5-10 membered heteroaryl is independently and optionally one, two. It may be substituted with 1 or 3 R ^6s , where R ⁶ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 cyanoalkyl or C _1-6 hydroxyalkyl.
W is a condensed cyclyl, a crosslinked cyclyl or a spirocyclyl, where the condensed cyclyl, the crosslinked cyclyl or the spirocyclyl is independently selected from N, O or S, 0, 1, 2, 3 or 4 Saturated or partially unsaturated 6-12 membered cyclyls containing heteroatoms, where W is optionally D, oxo (= O), F, Cl, Br, I, hydroxy, Amino, nitro, cyano, -C (= O) OR, -C (= O) NR ^a R ^b , -C (= NR) NR ^a R ^b , -NH-C (= NR) NR ^a R ^b ,- SO ₂ R, -SO ₂ NR ^a R ^b , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkyl amino, C _1-6 haloalkyl , C _1-6 cyanoalkyl and C _1-6 hydroxyalkyl may be substituted with 1, 2, 3, 4 or 5 substituents independently selected.
Here, each of R, Ra and R ^b is independently H, D, C _1-6 alkyl, C _1-6 haloalkyl or C _3-8 cycloalkyl, or R ^a and R ^b are ^. , Together with the N atoms to which they are attached, form 3-10 membered heterocyclyls, where the 3-10 membered heterocyclyls are optionally oxo (= O), D, F, Cl, Br. , I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 haloalkyl) or stereoisomers thereof, geometric isomers thereof, each other. Variants, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs.
[2] Het is a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, where each of the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl is independently and optionally. H, D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, carboxy and -C (= O) The compound according to Appendix [1], which may be substituted with NH ₂ .
[3] Het includes pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolysyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridylyl, pyridazole. Or pyrazinyl, where pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolysyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazil. , Pyridadinyl and each of pyrazinyl independently and optionally, H, D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, The compound according to any one of the appendices [1] to [2], which may be substituted with isopropoxy, trifluoromethyl, difluoromethyl, carboxy and -C (= O) NH ₂ .
[4] R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy or C _1-3 haloalkyl.
R ² is -OR or -NR ^a R ^b , and is
Here, each of R, Ra and R ^b is independently H, D, C _1-3 alkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl, or R ^a and R ^b are ^. , Together with the N atoms to which they are attached, form a 4- to 6-membered heterocyclyl, where the 4- to 6-membered heterocyclyls are optionally oxo (= O), D, F, Cl, Br. , I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl may be substituted.
Each of R ³ and R ⁴ is independently H, D, C _1-3 alkyl, C _1-3 hydroxyalkyl or C _1-3 haloalkyl, any one of the appendices [1] to [3]. The compound described in.
[5] R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl or trifluoroethyl. ,
R ² is -OR or -NR ^a R ^b , and is
Here, each of R, Ra and R ^b independently has H, D, methyl, ethyl, ⁿ -propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Or R ^a and R ^b , together with the N atom to which they are attached, from formulas (ia) to (i-k) :.

Forming a heterocyclyl selected from the heterocyclyl groups represented by
Here, the heterocyclyl group represented by the formulas (ia) to (ik) is optionally oxo (= O), D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, It may be substituted with methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl or trifluoroethyl.
Each of R ³ and R ⁴ is independently H, D, methyl, ethyl, n-propyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or 2-fluoroethyl, according to the appendices [1] to [4]. The compound according to any one item.
[6] R5 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl or a ^5-6 membered heteroaryl, where phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and Each of the 5-6 membered heteroaryls may be independently and optionally substituted with one, two or three R6s, where R6 ^{is H} , D, F, Cl. , Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy, C _1-3 cyanoalkyl or C _1-3 hydroxy The compound according to any one of the appendices [1] to [5], which is an alkyl.
[ ⁷ ] R5 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, frill, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl or pyridadinyl. Yes, where each of phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, frill, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl and pyridadinyl , Independently and optionally , substituted with one, two or three R6s ^{, where} R6 is H, D, F, Cl, Br, I, hydroxy, amino, nitro. , Cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, hydroxyethyl, cyanomethyl or cyanoethyl, Appendix [1]. The compound according to any one of [6].
[8] W has the following structure:

Have one of
Each of X ¹ , X ² and X ³ is independently bound, -CH _2- , -O- , -S- or -NH.
-And
Y is CH or N,
Each of r, s, t and n is 0, 1, 2 or 3 independently.
Each W is optionally D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, -C (= O) OH, -C (= O) NH ₂ , -C. (= NH) NH ₂ , -NH-C (= NH) NH ₂ , -SO ₂ CH ₃ , -SO ₂ C ₂ H ₅ , C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy , C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkyl, C _1-3 cyanoalkyl and C _1-3 hydroxyalkyl independently selected 1, 2, 3, 4 The compound according to any one of the appendices [1] to [7], which may be substituted with one or five substituents.
[9] W has the following structure:

Have one of
Each W is optionally D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, -C (= O) OH, -C (= O) NH ₂ , -C. (= NH) NH ₂ , -NH-C (= NH) NH ₂ , -SO ₂ CH ₃ , -SO ₂ C ₂ H ₅ , methyl, ethyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , 1, 2, 3, 4 or 5 independently selected from trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, methylamino, cyanomethyl and hydroxymethyl. Item 6. The compound according to any one of the appendices [1] to [8], which may be substituted with a substituent.
[10] Next structure:

The compound according to any one of the appendices [1] to [9] having one of the above, a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, etc. Metabolites, pharmaceutically acceptable salts or prodrugs.
[11] A pharmaceutical composition comprising the compound according to any one of claims 1 to 10.
[12] The pharmaceutical composition according to claim 11, further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof.
[13] The compound according to any one of the appendices [1] to [10] in the manufacture of a pharmaceutical agent for preventing, treating, treating or alleviating a disorder or disease controlled by acetyl-CoA carboxylase. Alternatively, use of the pharmaceutical composition according to the appendix [11] or [12].
[14] The use according to Appendix [13], wherein the disorder or disease controlled by the acetyl-CoA carboxylase is a metabolic disorder or a neoplastic disorder.
[15] The disorders or diseases controlled by the acetyl-CoA carboxylase include insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic steatohepatitis and non-alcoholic steatohepatitis. Use as described in Appendix [13].
[16] The neoplastic disorders include breast cancer, pancreatic cancer, renal cell cancer, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell bronchial cancer, endometrial cancer, and rectal colon. Use as described in Appendix [14], including cancer as well as pancreatic cancer.
[17] The item according to any one of the appendices [1] to [10], for use in preventing, treating, treating, or alleviating the disorder or disease controlled by the acetyl-CoA carboxylase. The compound or the pharmaceutical composition according to.
[18] The compound or pharmaceutical composition according to Appendix [17], wherein the disorder or disease controlled by the acetyl-CoA carboxylase is a metabolic disorder or a neoplastic disorder.
[19] The disorders or diseases controlled by the acetyl-CoA carboxylase include insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic steatohepatitis and non-alcoholic steatohepatitis. The compound or pharmaceutical composition according to the appendix [17].
[20] The neoplastic disorders include breast cancer, pancreatic cancer, renal cell cancer, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell bronchial cancer, endometrial cancer, and rectal colon. The compound or pharmaceutical composition according to Appendix [18], which comprises cancer as well as pancreatic cancer.
[21] A disease comprising administering to an affected body a therapeutically effective amount of the compound according to any one of the appendices [1] to [10] or the pharmaceutical composition according to the appendix [11] or [12]. A method of preventing, treating, treating, or alleviating a disorder or disease controlled by acetyl-CoA carboxylase in the body.
[22] The method according to appendix [21], wherein the disorder or disease controlled by the acetyl-CoA carboxylase is a metabolic disorder or a neoplastic disorder.
[23] The disorders or diseases controlled by the acetyl-CoA carboxylase include insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic steatohepatitis and non-alcoholic steatohepatitis. The method according to the appendix [21].
[24] The neoplastic disorders include breast cancer, pancreatic cancer, renal cell cancer, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell bronchial cancer, endometrial cancer, and rectal colon. 22. The method according to appendix [22], comprising cancer as well as pancreatic cancer.

Claims (16)

A compound having formula (I) or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof:

During the ceremony
Het is a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, where each of the 3-10 membered heterocyclyl and the 5-10 membered heteroaryl is independently and optionally H, D. , Oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, carboxy and -C (= O) NH May be replaced with ₂
R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl.
R ² is -OR or -NR ^a R ^b .
Each of R ³ and R ⁴ is independently H, D, C _1-6 alkyl, C _1-6 hydroxyalkyl or C _1-6 haloalkyl.
L is -O-, -O-methylene-, -O-ethylene-, -S- or -NH-, and
R ⁵ is a C _6-10 aryl or a 5-10 membered heteroaryl, where each of the C _6-10 aryl and the 5-10 membered heteroaryl is independently and optionally one, two. It may be substituted with 1 or 3 R ^6s , where R ⁶ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 cyanoalkyl or C _1-6 hydroxyalkyl.
W is a condensed cyclyl, a crosslinked cyclyl or a spirocyclyl, where the condensed cyclyl, the crosslinked cyclyl or the spirocyclyl is independently selected from N, O or S, 0, 1, 2, 3 or 4 Saturated or partially unsaturated 6-12 membered cyclyls containing heteroatoms, where W is optionally D, oxo (= O), F, Cl, Br, I, hydroxy, Amino, nitro, cyano, -C (= O) OR, -C (= O) NR ^a R ^b , -C (= NR) NR ^a R ^b , -NH-C (= NR) NR ^a R ^b ,- SO ₂ R, -SO ₂ NR ^a R ^b , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkyl amino, C _1-6 haloalkyl , C _1-6 cyanoalkyl and C _1-6 hydroxyalkyl may be substituted with 1, 2, 3, 4 or 5 substituents independently selected.
^Here , each of R, Ra and R ^b is independently H, D, C _1-6 alkyl, C _1-6 haloalkyl or C _3-8 cycloalkyl, or ^Ra and R ^b are. , Together with the N atoms to which they are attached, form 3-10 membered heterocyclyls, where the 3-10 membered heterocyclyls are optionally oxo (= O), D, F, Cl, Br. , I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 haloalkyl may be substituted. Het is a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, where each of the 5-6 membered heterocyclyl and the 5-6 membered heteroaryl is independently and optionally H, D. , Oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, carboxy and -C (= O) NH The compound according to claim 1, which may be substituted with ₂ . Het is pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolysyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl. Yes, where pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolysyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridylyl, pyridiyl. Each of the pyrazinyl, independently and optionally, H, D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, The compound according to any one of claims 1 to 2, which may be substituted with trifluoromethyl, difluoromethyl, carboxy and —C (= O) NH ₂ . R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy or C _1-3 haloalkyl.
R ² is -OR or -NR ^a R ^b .
^Here , each of R, Ra and R ^b is independently H, D, C _1-3 alkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl, or R ^a and R ^b are. , Together with the N atoms to which they are attached, form a 4- to 6-membered heterocyclyl, where the 4- to 6-membered heterocyclyls are optionally oxo (= O), D, F, Cl, Br. , I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl may be substituted.
The invention according to any one of claims 1 to 3, wherein each of R ³ and R ⁴ is independently H, D, C _1-3 alkyl, C _1-3 hydroxyalkyl or C _1-3 haloalkyl. Compound. R ¹ is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl or trifluoroethyl.
R ² is -OR or -NR ^a R ^b .
^{Here, each of R, Ra and R b independently} has H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Or R ^a and R ^b , together with the N atom to which they are attached, from formulas (ia) to (i-k) :.

Forming a heterocyclyl selected from the heterocyclyl groups represented by
Here, the heterocyclyl group represented by the formulas (ia) to (ik) is optionally oxo (= O), D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, It may be substituted with methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl or trifluoroethyl.
Any one of claims 1 to 4, wherein each of R ³ and R ⁴ is independently H, D, methyl, ethyl, n-propyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or 2-fluoroethyl. The compound described in the section. R5 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl or a ^5-6 membered heteroaryl, where phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and 5-6 Each of the member heteroaryls may be independently and optionally substituted with one, ^two or three ^R6s , where R6 is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy, C _1-3 cyanoalkyl or C _1-3 hydroxyalkyl. , The compound according to any one of claims 1 to 5. R5 is phenyl, naphthyl, 1,2,3,4 ^- tetrahydronaphthyl, imidazolyl, pyrazolyl, frill, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl or pyridadinyl. So, each of phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, frill, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl and pyridadinyl is independent. And optionally, it may be substituted with one, ^two or three ^R6s , where R6 is H, D, F, Cl, Br, I, hydroxy, amino, nitro, cyano, Any of claims 1 to 6, which are methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, hydroxyethyl, cyanomethyl or cyanoethyl. Or the compound according to item 1. W has the following structure:

Have one of
Each of X ¹ , X ² and X ³ is independently bound, -CH _2- , -O-, -S- or -NH-.
Y is CH or N,
Each of r, s, t and n is 0, 1, 2 or 3 independently.
Each W is optionally D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, -C (= O) OH, -C (= O) NH ₂ , -C. (= NH) NH ₂ , -NH-C (= NH) NH ₂ , -SO ₂ CH ₃ , -SO ₂ C ₂ H ₅ , C _1-3 alkyl, C _3-6 cycloalkyl, C _1-3 alkoxy , C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkyl, C _1-3 cyanoalkyl and C _1-3 hydroxyalkyl independently selected 1, 2, 3, 4 The compound according to any one of claims 1 to 7, which may be substituted with one or five substituents. W has the following structure:

Have one of
Each W is optionally D, oxo (= O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, -C (= O) OH, -C (= O) NH ₂ , -C. (= NH) NH ₂ , -NH-C (= NH) NH ₂ , -SO ₂ CH ₃ , -SO ₂ C ₂ H ₅ , methyl, ethyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , 1, 2, 3, 4 or 5 independently selected from trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, methylamino, cyanomethyl and hydroxymethyl. The compound according to any one of claims 1 to 8, which may be substituted with a substituent. Next structure:

The compound according to any one of claims 1 to 9, which has one of the above, or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, or pharmaceutical thereof. Tolerable salt: A pharmaceutical composition comprising the compound according to any one of claims 1 to 10. 11. The pharmaceutical composition of claim 11, further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof. The compound according to any one of claims 1 to 10 or claim 11 or for use in preventing, treating, treating, or alleviating a disorder or disease controlled by the acetyl-CoA carboxylase. 12. The pharmaceutical composition according to 12. The compound or pharmaceutical composition according to claim 13, wherein the disorder or disease controlled by the acetyl-CoA carboxylase is a metabolic disorder or a neoplastic disorder. The disorder or disease controlled by the acetyl-CoA carboxylase includes insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic steatohepatitis and non-alcoholic steatohepatitis, claim 13. The compound or pharmaceutical composition according to. The neoplastic disorders include breast cancer, pancreatic cancer, renal cell cancer, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell bronchial cancer, endometrial cancer, colorectal cancer and The compound or pharmaceutical composition of claim 14, comprising prostate cancer.